Tetrahydroisoquinolin-1-one derivative or salt thereof

ABSTRACT

[Problems] To provide a pharmaceutical, in particular a compound which can be used as a therapeutic agent for irritable bowel syndrome (IBS). 
     [Means for Solving Problems] It was found that a tetrahydroisoquinolin-1-one derivative having an amide group at the 4-position or a pharmaceutically acceptable salt thereof has an excellent bombesin 2 (BB2) receptor antagonistic action. It is also found that the tetrahydroisoquinolin-1-one derivative is highly effective on bowel movement disorders. From the above, the tetrahydroisoquinolin-1-one derivative of the present invention is useful as a therapeutic agent for diseases associated with a BB2 receptor, in particular IBS.

TECHNICAL FIELD

The present invention relates to a pharmaceutical, in particular, a tetrahydroisoquinolin-1-one derivative or a salt thereof, which is useful as a therapeutic agent for irritable bowel syndrome.

BACKGROUND ART

Irritable bowel syndrome (IBS) is a syndrome which causes chronic symptoms such as abdominal pain, bloating, and the like, bowel movement disorders such as diarrhea, constipation, and the like, defecation trouble, defecation straining, and the like. It is caused by functional abnormality of the lower digestive tract, mainly the large intestine, despite the absence of organic disorders such as inflammation, tumors, and the like, and is classified based on the conditions of stool into diarrhea-predominant, constipation-predominant, and alternating IBS which alternately repeats diarrhea and constipation. IBS is a disease which has a relatively high frequency occupying from 20 to 50% of bowel disease patients who consult outpatient cares, which is predominant in females with a male to female ratio of 1:2 regardless of race, and which has a high prevalence rate in the younger generation. Since mental stress correlates strongly with the state of the disease, it is regarded as a representative stress-related somatic disease and it is said that the stress management is important for the improvement of symptoms. Actually, it is known that abnormal motility of gastrointestinal tract is significantly accelerated and the symptoms are aggravated when emotional stress is applied to IBS patients. In addition, since the symptoms continue, a vicious circle is likely to form in which increased patient anxiety further aggravates the symptoms.

As the drug therapy of IBS, an anticholinergic is used for abdominal pain, and a tricyclic antidepressant for the improvement of pain threshold value reduction in the digestive tracts, and for the improvement of abnormal bowel motility, a stegnotic, a drug for controlling intestinal function, and the like in the case of diarrhea, and a saline cathartic and the like in the case of constipation, however these are merely symptomatic therapies and their effects are not clear. As an agent from which effects can be expected for both diarrhea and constipation, there is polycarbophil calcium, which regulates the hardness of feces by gelating in the intestines, however it exerts very limited effects because not only there is a bloating at the initial stage of its administration but also it requires time to exhibit the effects. Anxiolytics and antidepressants are used when anxiety and tension are considerably increased due to stress, however they are administered at a dose lower than the dose in the psychiatric field, so that there are cases in which the mental symptoms are not improved or cases in which these are improved but they do not exhibit any effects on the bowel movement disorder. Generally, among the symptoms of IBS, anxiolytics are effective for diarrhea and abdominal pain in some cases, but they have a tendency to exhibit little effect on constipation.

There are a 5-HT3 receptor antagonist alosetron and a 5-HT4 receptor agonist tegaserod as the agents, which have been drawing attention in recent years, and they are used in the diarrhea-predominant and the constipation-predominant, respectively. These agents improve the bowel movement by regulating the movement of intestines, and exhibit an effect quickly. However, though alosetron shows a relatively high improving rate of from 40 to 60% for abdominal symptoms and diarrhea, constipation occurs in 30 to 35% of the patients and it causes ischemic colitis (including mortal cases) as a serious side effect, so that its use is limited (Non-Patent Document 1). In addition, it cannot be said that the effect of tegaserod on the constipation-predominant is sufficient, and there is a possibility of causing tachyphylaxis (a phenomenon in which resistance is generated when a drug is repeatedly administered within a short period of time).

Apropos, when the living body receives a stress, it generates a hypothalamic-pituitary-adrenal system (HPA system) reaction, in which an adrenocorticotropic hormone (ACTH) is released through the secretion of a stress-related substance from the hypothalamus and a subsequent action upon the anterior hypophysis, and the ACTH released into the blood secretes corticosterone from the adrenal cortex, and thereby shows various stress responses such as increase in the blood pressure and the like. As the stress-related substance, corticotropin releasing hormone (CRH), bombesin (BB)/gastrin releasing peptide (GRP), vasopressin, neuropeptide Y, substance P, neurotensin, and the like are known. Secretion of these substances from the hypothalamus is accelerated when a stress is applied to an animal. Particularly regarding the CRH, it has been reported that it reinforces ACTH release and large bowel movement when administered to IBS patients (Non-Patent Document 2).

The bombesin/GRP as one of the stress-related substances is a brain-gut peptide and expresses various physiological actions via bombesin receptors. The bombesin receptor is classified into 3 subtypes of BB1, BB2 and BB3/BRS3 (bombesin receptor subtype-3), and as intrinsic ligands of mammals for the BB1 and BB2 receptors, neuromedin B and GRP have been identified respectively. It has been reported that the GRP and BB2 receptors are present ubiquitously in the brain, the digestive tracts, and the like, but GRP is markedly increased in the amygdala and hypothalamus when stress is applied to an animal (Non-Patent Document 3). In addition, it has been reported also that a BB2 receptor antagonist inhibits the increase in ACTH when administered into the cerebral ventricle in a restraint stress-added rat (Non-Patent Document 4).

As the role of the GRP/BB2 receptor in the digestive tract functions, it has been reported that it enhances the contraction in isolated human and rabbit ileum longitudinal muscle specimens (Non-Patent Documents 5 and 6), and enhances the water secretion in guinea pigs with the coexistence of a vasoactive intestinal peptide (VIP) (Non-Patent Document 7). In addition, it has been reported that BB2 receptor antagonists including RC-3095 that is a peptidic BB2 receptor antagonist, is effective for an abnormal bowel motility in a stress-induced defecation model. It has also been reported that, using an abdominal muscle contraction reaction as the index, RC-3095 is effective for an abdominal symptom in an abdominal pain model induced by large intestinal distension. Accordingly the BB2 receptor antagonist shows excellent efficacy on both the abdominal symptom and abnormal bowel motility (Patent Document 1).

As shown above, the BB2 receptor antagonist is expected to be a therapeutic agent for IBS, showing excellent efficacy on both the abdominal symptom and abnormal bowel motility.

Furthermore, since the bombesin/GRP also has a function as a cell growth factor and the expression of the GRP/BB2 receptor is increased in various cancer cells of lung cancer, prostate cancer, and the like, the efficacy of RC-3095 has been reported in a large number of antitumor tests (Non-Patent Documents 8 to 10). From this viewpoint, the BB2 receptor antagonist can also be expected to be effective against various cancers.

The tetrahydroisoquinolin-1-one derivative has been reported in Patent Documents 2 to 4.

Patent Document 2 describes that a 3,4-dihydroisoquinolin-1-one derivative represented by the following formula (A) has a caspase activating action and an apoptosis inducing action, and is effective for cancers, autoimmune diseases, rheumatoid arthritis, inflammatory bowel syndrome, psoriasis, and the like. However, there is no description of its antagonistic action on a bombesin type 2 receptor or of its efficacy regarding IBS.

(for the symbols in the formula, refer to the publication)

Patent Document 3 describes that a tetrahydroisoquinolin-1-one derivative represented by the following formula (B) is a ligand of an HDM2 protein, has an apoptosis inducing activity and a proliferation inhibitory activity, and is effective against cancers. However, there is no description of its antagonistic action on a bombesin type 2 receptor or of its efficacy regarding IBS.

(for the symbols in the formula, refer to the publication)

Patent Document 4 describes that a tetrahydroisoquinolin-1-one derivative represented by the following formula (C) is a neurotensin-2 (NT-2) receptor antagonist and is effective against pain. However, for R⁵ corresponding to R¹ of the present invention, there is no description on the R¹ group of the present invention. In addition, there is no description of its antagonistic action on a bombesin type 2 receptor or of its efficacy regarding IBS.

(wherein R⁵ means (C₁-C₈)alkyl which is optionally substituted with a group selected from trifluoromethyl, halogen, saturated or partially unsaturated (C₃-C₈)cycloalkyl, and (C₆-C₁₀)aryl. For the other symbols, refer to the publication.)

The compounds described in the following Tables 1 to 11 below are reported as Catalog Compounds. However, there is no description of the antagonistic action on a bombesin type 2 receptor and the efficacy for IBS, of these compounds. Further, in the following Tables, the abbreviations below are used. Me: Methyl, Et: Ethyl, iPr: Isopropyl, nBu: Normal Butyl, Ph: Phenyl.

TABLE 1

CAS Registry No. R^(a)R^(b)N— 931939-66-1

931315-65-0

902607-43-6 Me₂N— 902450-09-3 Ph—(CH₂)₂—NH— 891914-00-4 PhCH₂—NH— 891913-84-1

891913-76-1

891913-68-1

891913-28-3

891913-04-5

891912-88-2 EtNH— 891912-80-4

TABLE 2 891912-64-4

891912-56-4

891912-48-4

891912-40-6

891912-16-6

891912-08-6

891912-00-8

891911-84-5

891911-60-7

891911-52-7

891911-44-7

891911-36-4

TABLE 3 891911-29-8

891911-22-1

891911-07-2

891910-93-3

891910-86-4

891910-72-8

891910-65-9

891910-58-0

891910-23-9

891910-07-9

891909-99-2

891909-91-4 EtO—(CH₂)₃—NH— 891909-83-4

TABLE 4 891909-75-4

891909-67-4

891909-59-4 iPrO—(CH₂)₃—NH— 891909-51-6

891909-27-6 PhN(Et)—(CH₂)₃—NH— 891909-11-8

891909-03-8

891908-95-5

891908-55-7 Et₂N— 891907-99-6

891907-91-8

891907-83-8

891907-75-8

891907-43-0 MeO—(CH₂)₃—NH— 891907-35-0 nBuNH— 891907-27-0 iPrNH— 891907-19-0

891907-11-2 MeO—(CH₂)₂—NH—

TABLE 5 891907-03-2

891906-95-9

891906-87-9

891906-79-9

891906-71-1

891906-55-1

891906-39-1

891905-75-2

891904-87-3

TABLE 6

CAS Registry No. R^(a)R^(b)N— 685520-62-1

685520-61-0

442858-62-0 EtO₂C—CH₂—NH— 442858-61-9

442858-27-7 MeO₂C—(CH₃)₂—NH— 442858-05-1 MeO₂C—CH₂—NH— 442858-04-0

442857-76-3

442857-73-0

442856-86-2

442856-85-1

442856-80-6 Et₂N—

TABLE 7 442856-71-5

442856-34-0

442856-31-7

442856-30-6

442856-29-3 iPrNH— 442856-28-2

442856-17-9

442856-15-7 PhN(Et)-(CH₂)₃—NH— 442855-08-5

442854-93-5

442854-92-4

442854-57-1 MeO—(CH₂)₂—NH— 442854-41-3

TABLE 8

CAS Registry No. R^(a)R^(b)N— 685520-63-2

442859-46-3

442859-42-9

442859-40-7

442859-39-4

442859-38-3

442859-36-1

442859-27-0

442859-26-9

TABLE 9 442859-25-8

442859-20-3 Et₂N— 442859-13-4

442859-12-3

442859-11-2 MeO—(CH₂)₃—NH— 442859-09-8 nBuN(Et)— 442859-06-5

442859-05-4 nBuNH— 442859-03-2

442859-02-1 EtO₂C—CH₂—NH— 442859-01-0 MeO—(CH₂)₂—NH— 442858-99-3 nBuN(Me)NH— 442858-98-2

442858-93-7

442858-91-5 PhCH₂N(Me)— 442858-86-8

442858-79-9

TABLE 10 442858-77-7

442858-76-6

442858-72-2

442858-67-5

442858-56-2 iPrNH— 442858-55-1

TABLE 11

CAS Registry No. R^(a)R^(b)N— 442888-72-4

442888-70-2

442888-60-0

442888-49-5

442888-41-7

442888-39-3

442888-37-1

442888-35-9

Non-Patent Document 1: “American Journal of Gastroenterology”, (USA), 2003, vol. 98, p. 750-758

Non-Patent Document 2: “Gut”, (England), 1998, vol. 42, p. 845-849

Non-Patent Document 3: “The Journal of Neuroscience”, (USA), 1998, vol. 18, p. 4758-4766

Non-Patent Document 4: “Life Sciences”, (Holland), 2002, vol. 70, p. 2953-2966

Non-Patent Document 5: “Gastroenterology”, (USA), 1991, vol. 100, p. 980-985

Non-Patent Document 6: “Neurogastroenterology and Motility”, (England), 1997, vol. 9, p. 265-270

Non-Patent Document 7: “Annals of the New York Academy of Science”, (USA), 2000, vol. 921, p. 420-424

Non-Patent Document 8: “Cancer”, (USA), 1998, vol. 83, p. 1335-1343

Non-Patent Document 9: “British Journal of Cancer”, 2000, vol. 83, p. 906-913,

Non-Patent Document 10: “Cancer”, (USA), 2000, vol. 88, p. 1384-1392

Patent Document 1: Pamphlet of International Publication No. 2006/115135

Patent Document 2: Pamphlet of International Publication No. 2004/04727

Patent Document 3: Pamphlet of International Publication No. 2006/97323

Patent Document 4: Pamphlet of International Publication No. 03/29221

DISCLOSURE OF THE INVENTION Problem that the Invention is to Solve

It is an object of the present invention to provide a novel pharmaceutical having a BB2 receptor antagonistic action, in particular, a novel compound which is useful as a therapeutic agent for IBS.

Means for Solving the Problems

The present inventors have conducted extensive studies on BB2 receptor antagonists, and as a result, we have found that a novel tetrahydroisoquinolin-1-one derivative having an amide group as a substituent at the 4-position has an excellent BB2 receptor antagonistic action, thus completing the present invention.

Namely the present invention relates to a tetrahydroisoquinolin-1-one derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof:

[the symbols in the formula represent the following meanings:

R¹: lower alkylene-OH, lower alkylene-N(R⁰)(R⁶), lower alkylene-CO₂R^(o), cycloalkyl, cycloalkenyl, aryl, heterocyclic group, -(lower alkylene substituted with —OR⁰)-aryl or lower alkylene-heterocyclic group,

wherein the lower alkylene, cycloalkyl, cycloalkenyl, aryl and heterocyclic group in R¹ may each be substituted,

R⁰: the same as or different from each other, each representing —H or lower alkyl,

R⁶: R⁰, —C(O)—R⁰, —CO₂-lower alkyl or —S(O)₂-lower alkyl,

R²: lower alkyl, lower alkylene-OR^(o), lower alkylene-aryl, lower alkylene-heterocyclic group, lower alkylene-N(R⁰)CO-aryl, lower alkylene-O-lower alkylene-aryl, —CO₂R^(o), —C(O)N(R⁰)₂, —C(O)N(R⁰)-aryl, —C(O)N(R⁰)-lower alkylene-aryl, aryl or heterocyclic group,

wherein the aryl and heterocyclic group in R² may each be substituted,

R³: —H or lower alkyl,

or R² and R³ may be combined to form C₂₋₆ alkylene,

R⁴: —N(R⁷)(R⁸), —N(R⁰)—OH, —N(R⁰)—N(R⁰)(R⁷), —N(R⁰)—N(R⁰)(R⁷), —N(R⁰)—S(O)₂-aryl, or —N(R⁰)—S(O)₂—R⁷,

wherein the aryl in R⁴ may be substituted,

R⁷: lower alkyl, halogeno-lower alkyl, lower alkylene-CN, lower alkylene-OR⁰, lower alkylene-CO₂R⁰, lower alkylene-C(O)N(R⁰)₂, lower alkylene-C(O)N(R⁰)N(R⁰)₂, lower alkylene-C(═NH)NH₂, lower alkylene-C(═NOH)NH₂, heteroaryl, lower alkylene-X-aryl, or lower alkylene-X-heterocyclic group,

wherein the lower alkylene, aryl, heteroaryl, and heterocyclic group in R⁷ may each be substituted,

X: single bond, —O—, —C(O)—, —N(R⁰)—, —S(O)_(p)—, or *—C(O)N(R⁰)—,

wherein * in X represents a bond to lower alkylene,

m: an integer of 0 to 3,

p: an integer of 0 to 2,

R⁸: —H or lower alkyl,

or R⁷ and R⁸ may be combined to form lower alkylene-N(R⁹)-lower alkylene, lower alkylene-CH(R⁹)-lower alkylene, lower alkylene-arylene-lower alkylene, or lower alkylene-arylene-C(O)—,

R⁹: aryl and heteroaryl which may each be substituted,

R¹⁰: —H, lower alkyl, or —C(O)R⁰,

R⁵: lower alkyl, halogeno-lower alkyl, halogen, nitro, —OR⁰, —O-halogeno-lower alkyl, —N(R⁰)₂, —O-lower alkylene-CO₂R⁰, or —O-lower alkylene-aryl,

wherein the aryl in R⁵ may be substituted,

provided that, when R⁴ is —N(R⁷)(R⁸),

(1) a compound wherein R¹ is unsubstituted cyclopentyl and R² is unsubstituted 2-thienyl;

(2) a compound wherein R¹ is unsubstituted cyclohexyl and R² is 4-methoxyphenyl;

(3) a compound wherein R¹ is 4-methoxyphenyl and R² is 4-methoxyphenyl; and

(4) a compound wherein R¹ is (morpholin-4-yl)ethyl and R² is 4-ethoxyphenyl are excluded,

furthermore, 2,3-bis(4-chlorophenyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

3-(4-chlorobenzyl)-2-(4-chlorophenyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

3-[3,5-bis(trifluoromethyl)phenyl]-2-cyclopropyl-N-(2-furylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

3-[3,5-bis(trifluoromethyl)phenyl]-2-cyclopropyl-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

ethyl 3- {3-[3,5-bis(trifluoromethyl)phenyl]-4-{[2-(4-methoxyphenyl)ethyl]carbamoyl}-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl}propanoate,

N-benzyl-3-[3,5-bis(trifluoromethyl)phenyl]-1-oxo-2-(tetrahydrofuran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

3-[3,5-bis(trifluoromethyl)phenyl]-N-(2-methoxyethyl)-2-(2-morpholin-4-ylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

3-[3,5-bis(trifluoromethyl)phenyl]-2-(2-furylmethyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

3-[3,5-bis(trifluoromethyl)phenyl]-N-(2-furylmethyl)-2-(2-morpholin-4-ylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and

(4-chlorophenyl)[3-(4-chlorophenyl)-4-[(2-methoxyethyl)carbamoyl]-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl]acetic acid

are excluded. The symbols hereinafter represent the same meanings].

Further, the present application relates to a pharmaceutical comprising a tetrahydroisoquinolin-1-one derivative represented by the general formula (I) or a salt thereof as an active ingredient, in particular a BB2 receptor antagonist, a therapeutic agent for irritable bowel syndrome or a therapeutic agent for cancers.

Furthermore, the present application relates to the use of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a BB2 receptor antagonist, a therapeutic agent for irritable bowel syndrome, or a therapeutic agent for cancers, and to a method for treating irritable bowel syndrome or cancers, comprising administering to a patient an effective amount of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.

Namely, the present application relates to: (1) a pharmaceutical composition comprising the compound described in the general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,

(2) the pharmaceutical composition as described in (1), which is a BB2 receptor antagonist,

(3) the pharmaceutical composition as described in (1), which is a therapeutic agent for irritable bowel syndrome,

(4) the pharmaceutical composition as described in (1), which is a therapeutic agent for cancers,

(5) use of the compound as described in the general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a BB2 receptor antagonist, a therapeutic agent for irritable bowel syndrome, or a therapeutic agent for cancers, and

(6) a method for treating irritable bowel syndrome or cancers, comprising administering to a patient a therapeutically effective amount of the compound as described in the general formula (I) or a pharmaceutically acceptable salt thereof.

EFFECTS OF THE INVENTION

The compound of the present invention is useful as a therapeutic agent for IBS since it has an excellent antagonistic action on a BB2 receptor.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in more detail as follows.

The “lower alkyl” is preferably a linear or branched alkyl having 1 to 6 carbon atoms (which is hereinafter simply referred to as C₁₋₆), and specifically, it includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl group, and the like. More preferably, it is C₁₋₄ alkyl, and more preferably, it includes methyl, ethyl, n-propyl, and isopropyl.

The “lower alkylene” is preferably a linear or branched C₁₋₆ alkylene, and specifically, it includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene group, and the like. Preferably, it is C₁₋₄ alkylene, and more preferably, it includes methylene, ethylene, and trimethylene.

The “halogen” means F, Cl, Br, or I.

The “halogeno-lower alkyl” refers to C₁₋₆ alkyl substituted with one or more halogens. It is preferably lower alkyl substituted with 1 to 5 halogens, and more preferably trifluoromethyl.

The “halogeno-lower alkylene” refers to C₁₋₆ alkylene substituted with one or more halogens. It is preferably lower alkylene substituted with 1 to 5 halogens, and more preferably, it includes difluoromethylene and difluoroethylene.

The “cycloalkyl” refers to a C₃₋₁₀ saturated hydrocarbon ring group, which may have a bridge. Specifically, it includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl group, and the like. It is preferably C₃₋₈ cycloalkyl, and more preferably C₃₋₆ cycloalkyl, and even more preferably, it includes cyclopentyl and cyclohexyl.

The “cycloalkenyl” refers to C₃₋₁₅ cycloalkenyl, which may have a bridge, and it includes a ring group condensed with a benzene ring at a double bond site. Specifically, it includes cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, 1-tetrahydronaphthyl, 1-indenyl, 9-fluorenyl group, and the like. Preferably, it is C₅₋₁₀ cycloalkenyl, and more preferably, it includes cyclopentenyl and cyclohexenyl.

The “aryl” refers to a C₆₋₁₄ monocyclic to tricyclic aromatic hydrocarbon ring group, and preferably, it includes phenyl and naphthyl, and more preferably phenyl.

The “arylene” refers to a divalent group formed by removing an arbitrary hydrogen atom from aryl, and it is preferably phenylene, and more preferably orthophenylene.

The “heteroaryl” means a ring group consisting of i) monocyclic 5- to 6-membered heteroaryl containing 1 to 4 hetero atoms selected from O, S, and N, and ii) bicyclic a 8- to 10-membered heterocycle and a tricyclic 11- to 14-membered heterocycle, each containing 1 to 5 hetero atoms selected from O, S, and N, which are formed by condensation of the monocyclic heteroaryl, and one or two rings selected from the group consisting of monocyclic heteroaryl and a benzene ring. The ring atom S or N may be oxidized to form an oxide or a dioxide.

The “heteroaryl” preferably includes pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, indolyl, indazolyl, benzoimidazolyl, imidazopyridyl, quinolyl, quinazolyl, quinoxalinyl, naphthylidinyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, and carbazolyl, and more preferably pyrrolyl, pyridyl, furyl, thienyl, and thiazolyl.

The “heterocyclic group” means a ring group consisting of i) a monocyclic 3- to 8-membered (preferably 5- to 7-membered) heterocycle containing 1 to 4 hetero atoms selected from O, S, and N, and ii) a bicyclic 8- to 14-membered (preferably 9- to 11-membered) heterocycle and a tricyclic 11- to 20-membered (preferably 12- to 15-membered) heterocycle, each containing 1 to 5 hetero atoms selected from O, S, and N, which are formed by the condensation of the monocyclic heterocycle, and one or two rings selected from the group consisting of a monocyclic heterocycle, a benzene ring, C₅₋₈ cycloalkane, and C₅₋₈ cycloalkene. The ring atom S or N may be oxidized to form an oxide or a dioxide, or may have a bridge.

The “heterocyclic group” preferably includes aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxiranyl, oxetanyl, tetrahydropyranyl, tetrahydropyranyl, morpholinyl, homomorpholinyl, tetrahydrothienyl, tetrahydrothiopyranyl, thiomorpholinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, imidazopyridyl, quinolyl, quinazolyl, quinoxalinyl, naphthylidinyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, dihydroindolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, tetrahydroquinolyl, benzodioxolyl, dihydrobenzodioxynyl, dihydrobenzoxazinyl, tetrahydronaphthylidinyl, carbazolyl, and quinuclidinyl, and more preferably pyrrolidyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolyl, pyridyl, furyl, thienyl, and thiazolyl.

The expression “which may be substituted” means “which is not substituted” or “which is substituted with 1 to 5 substituents which may be the same as or different from each other”. The expression “which is substituted” refers to “which is substituted with 1 to 5 substituents which are the same as or different from each other”. Further, if a plurality of substituents are contained, the substituents may be the same as or different from each other.

The substituent for the “lower alkylene” which may be substituted in R¹ is preferably a group selected from Group G¹, and more preferably —OH or phenyl.

Group G¹: halogen, —OR⁰, —N(R⁰)(R⁶), and aryl.

Provided that, the “aryl” in Group G¹ may be substituted with a group selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, —OR⁰, and —O-halogeno-lower alkyl.

The substituent for the “cycloalkyl”, “cycloalkenyl”, and “heterocyclic group” which may be each substituted in R¹ is preferably a group selected from Group G², more preferably —OR⁰, —CO₂R^(o), —N(R⁰)₂, —N(R⁰)C(O)R^(o), —N(R⁰)C(O)-lower alkylene—OR⁰, or —N(R⁰)S(O)₂-lower alkyl, and even more preferably —OR^(o), —N(R^(o))C(O)R^(o), or —N(R^(o))S(O)₂-lower alkyl.

Group G²: halogen, lower alkyl, halogeno-lower alkyl, lower alkylene-OR⁰, —OR⁰, —O-halogeno-lower alkyl, —N(R⁰)₂, —N(R⁰)-lower alkylene-OR⁰, —N(R⁰)-lower alkylene-CO₂R^(o), —N(R⁰)C(O)R^(o), —N(R⁰)C(O)OR⁰, —N(R⁰)C(O)-aryl, —N(R⁰)C(O)-lower alkylene-OR^(o), —N(R⁰)C(O)-lower alkylene-N(R⁰)₂, —N(R⁰)C(O)N(R⁰)₂, —N(R⁰)C(═NR⁰)-lower alkyl, —N(R⁰)S(O)₂-lower alkyl, —N(lower alkylene-OR⁰)—S(O)₂-lower alkyl, —N(lower alkylene-CO₂R^(o))—S(O)₂-lower alkyl, —N(R⁰)S(O)₂-lower alkylene-CO₂R^(o), —N(R⁰)S(O)₂-lower alkylene-S(O)₂-lower alkyl, —N(R⁰)S(O)₂-aryl, —N(R⁰)S(O)₂N(R⁰)₂, —S(O)₂-lower alkyl, —CO₂R^(o), —CO₂-lower alkylene-Si(lower alkyl)₃, —C(O)N(R⁰)₂, —C(O)N(R⁰)-lower alkylene-OR^(o), —C(O)N(R⁰)-lower alkylene-N(R⁰)₂, —C(O)N(R⁰)-lower alkylene-CO₂R^(o), —C(O)N(R⁰)—O-lower alkylene-heterocyclic group, heterocyclic group, —C(O)R⁰, —C(O)-lower alkylene-OR⁰, —C(O)-lower alkylene-N(R⁰)₂, —C(O)-heterocyclic group, and oxo.

Provided that the “aryl” and the “heterocyclic group” in Group G² may be each substituted with a group selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, —OR⁰, —O-halogeno-lower alkyl, and oxo.

The substituent for the “aryl” which may be substituted in R¹ is preferably a group selected from Group G³, and more preferably —OR⁰ or lower alkylene-OR⁰.

Group G³: halogen, lower alkyl, halogeno-lower alkyl, —OR⁰, —O-halogeno-lower alkyl, lower alkylene-OR⁰, and —CO₂R^(o).

The substituent for the “aryl” and the “heterocyclic group” which may be substituted in R² is preferably a group selected from Group G⁴, more preferably halogen, lower alkyl, or —OR⁰, and even more preferably halogen.

Group G⁴: halogen, —CN, nitro, lower alkyl, halogeno-lower alkyl, —OR⁰, —N(R⁰)₂, —CO₂R⁰, —C(O)N(R⁰)₂, —OS(O)₂-lower alkyl, and oxo.

The substituent for the “lower alkylene” which may be substituted in R⁷ is preferably a group selected from Group G⁵, more preferably halogen.

Group G⁵: halogen, —OR⁰, —N(R⁰)₂, and aryl.

Provided that the “aryl” in Group G⁵ may be substituted with a group selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, —OR⁰, and —O-halogeno-lower alkyl.

The substituent for the “aryl” and the “heterocyclic group” which may each be substituted in R⁷ is preferably a group selected from Group G⁶, and more preferably halogen, —OR⁰, lower alkylene-OR⁰, —CO₂R⁰, lower alkylene-CO₂R⁰, —O-lower alkylene-CO₂R⁰, or oxo.

Group G⁶: halogen, lower alkyl which may be substituted with —OR⁰, halogeno-lower alkyl which may be substituted with —OR⁰, —OR⁰, —CN, —N(R⁰)₂, —CO₂R⁰, —CO₂-lower alkylene-aryl, —C(O)N(R⁰)₂, lower alkylene-OC(O)R⁰, lower alkylene-OC(O)aryl, lower alkylene-CO₂R⁰, halogeno-lower alkylene-CO₂R⁰, lower alkylene-CO₂-lower alkylene-aryl, lower alkylene-C(O)N(R⁰)₂, halogeno-lower alkylene-C(O)N(R⁰)₂, —O-lower alkylene-CO₂R⁰, —O-lower alkylene-CO₂-lower alkylene-aryl, —O-lower alkylene-C(O)N(R⁰)₂, —O-halogeno-lower alkylene-CO₂R⁰, —O-halogeno-lower alkylene-C(O)N(R⁰)₂, —C(O)N(R⁰)S(O)₂-lower alkyl, lower alkylene-C(O)N(R⁰)S(O)₂-lower alkyl, —S(O)₂-lower alkyl, —S(O)₂N(R⁰)₂, heterocyclic group, —C(═NH)NH₂, —C(—NH)═NO—C(O)O—C₁₋₁₀ alkyl, —C(═NOH)NH₂, —C(O)N═C(N(R)₂)₂, —N(R⁰)C(O)R⁰, —N(R⁰)C(O)-lower alkylene-OR⁰, —N(R⁰)C(O)OR⁰, —N(R⁰)S(O)₂-lower alkyl, —C(aryl)₃, and oxo.

Provided that the “aryl” and the “heterocyclic group” in Group G⁶ may each be substituted with a group selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, —OR⁰, —O-halogeno-lower alkyl, oxo, and thioxo (═S).

The substituent for the “aryl” which may be substituted in R⁴; and the substituent for the “heteroaryl” which may be substituted in R⁷ are preferably a group selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, —OR⁰, and —O-halogeno-lower alkyl.

The substituent for the “aryl” and “heteroaryl” which may be each substituted in R⁹ is preferably a group selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, —OR⁰, and —O-halogeno-lower alkyl.

The substituent for the “aryl” which may each be substituted in R⁵ is preferably a group selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, —OR⁰, and —O-halogeno-lower alkyl.

Preferred embodiments of the present invention will be described below.

(a) R¹ is preferably -(lower alkylene which may be substituted)-OH, or cycloalkyl, aryl, or a heterocyclic group, which may each be substituted. More preferably, it is (lower alkylene which may be substituted)-OH, or cyclopentyl, cyclohexyl, phenyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidyl, or piperidyl, which may be each substituted. More preferably, it is (lower alkylene which may be substituted with a group selected from the group consisting of phenyl which may be substituted with halogen, lower alkyl, or —OR⁰, and —OH)—OH, or cycloalkyl substituted with a group selected from the group consisting of —OR^(o), —N(R^(o))₂, —N(R^(o))C(O)R^(o), —N(R^(o))C(O)-lower alkylene-OR^(o), —N(R)S(O)₂-lower alkyl, and a heterocyclic group. Even more preferably, it is (lower alkylene which may be substituted with a group selected from the group consisting of phenyl which may be substituted with halogen, lower alkyl or —OR⁰, and —OH)—OH, or cyclopentyl or cyclohexyl, which is each substituted with a group selected from the group consisting of —OR^(o), —N(R^(o))₂, —N(R^(o))C(O)R^(o), —N(R^(o))C(O)-lower alkylene-OR^(o), —N(R^(o))S(O)₂-lower alkyl and a heterocyclic group. Particularly preferably, it is cyclohexyl substituted with a group selected from the group consisting of —OR^(o), —N(R^(o))C(O)R^(o), and —N(R^(o))S(O)₂-lower alkyl.

(b) R² is preferably aryl which may be substituted, and more preferably phenyl which may be substituted with halogen, lower alkyl, or —OR⁰, and even more preferably phenyl substituted with halogen.

(c) R³ is preferably —H.

(d) R⁴ is preferably —N(R⁰)-lower alkylene-(aryl or heteroaryl, which may be each substituted) or —N(R⁰)—O-lower alkylene-(aryl or heteroaryl, which may be each substituted). More preferably, it is —NH-lower alkylene-(phenyl, pyridyl, N-oxidopyridyl, thienyl, or thiazolyl, which may each be substituted) or —NH—O-lower alkylene-(phenyl, pyridyl, N-oxidopyridyl, thienyl, or thiazolyl, which may be each substituted). More preferably, it is —NH-lower alkylene-(phenyl, pyridyl, N-oxidopyridyl, thienyl, or thiazolyl, which may each be substituted with a group selected from the group consisting of halogen, —OR⁰, lower alkylene-OR⁰, —CO₂R⁰, lower alkylene-CO₂R⁰, and —O-lower)alkylene-CO₂R⁰) or —NH—O-lower alkylene-(phenyl, pyridyl, N-oxidopyridyl, thienyl, or thiazolyl, which may each be substituted with a group selected from the group consisting of halogen, —OR⁰, lower alkylene-OR⁰, —CO₂R⁰, lower alkylene-CO₂R⁰, and —O-lower alkylene-CO₂R⁰). Even more preferably, it is —NH-lower alkylene-(phenyl which may be substituted with a group selected from the group consisting of halogen, —OR⁰, lower alkylene-OR⁰, —CO₂R⁰, lower alkylene-CO₂R⁰, and —O-lower alkylene-CO₂R⁰) or —NH—O-lower alkylene-(phenyl which may be substituted with a group selected from the group consisting of halogen, —OR⁰, lower alkylene-OR⁰, —CO₂R⁰, lower alkylene-CO₂R⁰, and —O-lower alkylene-CO₂R⁰).

(e) R⁵ is preferably halogen or —OR⁰.

(f) m is preferably 0 or 1, and more preferably 0.

In further preferred embodiments, the compounds having any combination of each of the preferable groups as described in (a) to (f) above are preferred.

Furthermore, other preferred embodiments for the compound of the present invention represented by the general formula (I) are shown below.

(1) A compound represented by the general formula (I), wherein R³ is —H.

(2) The compound as described in (1), wherein R² is phenyl which may be substituted with halogen, lower alkyl, or —OR⁰.

(3) The compound as described in (2), wherein R⁴ is —N(R⁰)-lower alkylene-(aryl or heteroaryl, which may each be substituted), or —N(R⁰)—O-lower alkylene-(aryl or heteroaryl, which may each be substituted).

(4) The compound as described in (3), wherein R¹ is (lower alkylene which may be substituted with a group selected from the group consisting of phenyl which may be substituted with halogen, lower alkyl or —OR⁰, and —OH)—OH; or cycloalkyl substituted with a group selected from the group consisting of —OR⁰, —N(R⁰)₂, —N(R⁰)C(O)R⁰, —N(R⁰)-lower alkylene-OR⁰, —N(R⁰)S(O)₂-lower alkyl, and a heterocyclic group.

(5) A compound represented by the general formula (I) selected from the group consisting of:

(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-N-[(1-oxidopyridin-2-yl)methoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

3-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}benzoic acid,

(4-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenyl)acetic acid,

(3-{[({[(3R,4R)-3-(2,4-dichlorophenyl-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetic acid,

{3-[2-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]phenyl}(difluoro)acetic acid,

(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-N-(2-{3-[(methylsulfonyl)carbamoyl]phenyl}ethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

{4-[2-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]phenyl}acetic acid, and

4-(3-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)butanoic acid;

or a pharmaceutically acceptable salt thereof.

Furthermore, in the present specification, the “irritable bowel syndrome” (which is hereinafter referred to as IBS) includes diarrhea type IBS, constipation type IBS, and alternating type IBS. The disease to which the therapeutic agent of the present invention is applied is preferably diarrhea type IBS or alternating type IBS, and particularly preferably diarrhea type IBS.

The compounds of the present invention may exist in the form of other tautomers or geometrical isomers depending on the kind of the substituents. In the present specification, the compound may be described in only one form of an isomer, but the present invention includes the isomers, an isolated form or a mixture of the isomers.

Furthermore, the compound (I) may have asymmetric carbons or axial asymmetries, and correspondingly, it may exist in the form of optical isomers such as an (R)-form, an (S)-form, and the like. The compound of the present invention includes both a mixture and an isolated form of these optical isomers.

In addition, a pharmaceutically acceptable prodrug of the compound (I) is also included in the present invention. The pharmaceutically acceptable prodrug refers to a compound, having a group which can be converted into an amino group, OH, CO₂H, and the like of the present invention, by solvolysis or under a physiological condition. Examples of the group which forms the prodrug include those as described in Prog. Med., 5, 2157-2161 (1985), or “Pharmaceutical Research and Development” (Hirokawa Publishing Company, 1990), vol. 7, Drug Design, 163-198.

Furthermore, the compound of the present invention may form an acid-addition salt or a salt with a base, depending on the kind of the substituents, and these salts are included in the present invention as long as they are pharmaceutically acceptable salts. Specifically, examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, or the like, and salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and the like, and with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and the like, ammonium salts.

In addition, the present invention also includes various hydrates and solvates, and polymorphism of the compound of the present invention and a pharmaceutically acceptable salt thereof. Furthermore, the present invention also includes the compounds that are labeled with various radioactive or non-radioactive isotopes.

(Production Process)

The compound of the present invention and a pharmaceutically acceptable salt thereof may be prepared by applying various known synthetic methods, by the use of the characteristics based on their basic backbones or the kind of the substituents. Here, depending on the kind of the functional groups, it is in some cases effective from the viewpoint of the preparation techniques to substitute the functional group with an appropriate protecting group (a group which may be easily converted into the functional group), during the steps from starting materials to intermediates. Examples of such functional groups include an amino group, a hydroxyl group, a carboxyl group, and the like, and examples of a protecting group thereof include those as described in “Protective Groups in Organic Synthesis” (3^(rd) edition, 1999), edited by Greene and Wuts, which may be optionally selected and used in response to the reaction conditions. By such a method, a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then, if desired, removing the protecting group.

In addition, a prodrug of the compound (I) can be prepared by introducing a specific group during the steps from starting materials to intermediates, in the same manner as for the aforementioned protecting groups, or by carrying out the reaction using the obtained compound (I). The reaction may be carried out by employing a method known to a person skilled in the art, such as general esterification, amidation, and dehydration.

Hereinbelow, the representative production processes of the compounds of the present invention will be described. Each of the production processes can also be carried out with reference to the reference documents attached to the present description. Further, the production processes of the present invention are not limited to the examples as shown below.

(Production Process 1)

This production process is a process for obtaining the compound (I) of the present invention by subjecting a carboxylic acid compound (1) and an amine compound (2) to amidation.

The reaction can be carried out using equivalent amounts of the carboxylic acid compound (1) and the amine compound (2), or an excess amount of either, and stirring them from under cooling to under heating, preferably at −20° C. to 60° C., usually for 0.1 hour to 5 days, in a solvent which is inert to the reaction, in the presence of a condensing agent. The solvent as used herein is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, and the like, halogenated hydrocarbons, such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, dimethoxyethane, and the like, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidin-2-one (NMP), dimethyl sulfoxide (DMSO), ethyl acetate, acetonitrile, water, and the like, or mixture thereof. Examples of the condensing agent include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), dicyclohexylcarbodiimide, 1,1′-carbonyldiimidazole (CDI), diphenyl phosphoryl azide, phosphorous oxychloride, and the like, but are not limited to these. An additive (for example, 1-hydroxybenzotriazole (HOBt), and the like) may be preferable for the reaction in some cases. It may be advantageous for the smooth progress of the reaction to carry out the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethyl-4-aminopyridine (DMAP), and the like, or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, and the like in some cases.

In addition, a process in which the carboxylic acid compound (1) is derived into a reactive derivative, and then reacted with the amine compound (2) can also be used. Examples of the reactive derivative of the carboxylic acid as used herein include an acid halide obtained by the reaction with a halogenating agent such as phosphorous oxychloride, thionyl chloride, and the like, a mixed acid anhydride obtained by the reaction with isobutyl chloroformate, or the like, an active ester obtained by the condensation with 1-hydroxybenzotriazole or the like, and others. The reaction of the reactive derivative and the amine compound (2) can be carried out from under cooling to under heating, preferably at −20° C. to 60° C., in a solvent which is inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, and the like.

Production Process 2: Other Production Processes

Furthermore, some compounds represented by the formula (I) can also be prepared by subjecting the compound of the present invention obtained as above to any combination of the processes that are usually employed by a skilled person in the art, such as conventional amidation, hydrolysis, N-oxidation, reductive amination, sulfonylation, oxidation, reduction, N-alkylation, O-alkylation, and the like. For example, they can be prepared by the reactions as below, the methods described in Examples to be described later, a method apparent to a skilled person in the art, or a modified method thereof.

2-1: Amidation

An amide compound can be obtained by subjecting a carboxylic acid compound and an amine compound to amidation.

The amidation can be carried out in the same manner as in Production Process 1.

2-2: Hydrolysis

A compound having a carboxyl group can be prepared by hydrolyzing a compound having an ester group.

The reaction can be carried out from under cooling to under heating in a solvent such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, DMF, DMA, NMP, DMSO, pyridine, water, and the like in the presence of an acid including mineral acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, and the like, and organic acids such as formic acid, acetic acid, and the like; or in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, ammonia, and the like.

2-3: N-Oxidation

An N-oxide compound can be prepared by oxidating the nitrogen atom of a heterocycle having a nitrogen atom, such as pyridine and the like, with various oxidants.

The reaction can be carried out from under cooling, at room temperature to under heating, using an equivalent amount or excess amount of m-chloroperbenzoic acid, peracetic acid, aqueous hydrogen peroxide, and the like as an oxidant, in a solvent such as halogenated hydrocarbons, acetic acid, water, and the like.

2-4: Reductive Amination

An amine compound can be alkylated by reducing an imine compound which is prepared from a primary or secondary amine compound and a carbonyl compound.

The reaction can be carried out using equivalent amounts of an amine compound and a carbonyl compound, or an excessive amount of either thereof, in the presence of a reducing agent, in a solvent such as halogenated hydrocarbons, alcohols, ethers, and the like. As the reducing agent, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, and the like can be used. The reaction may be preferably carried out in the presence of an acid such as acetic acid, hydrochloric acid, titanium(IV)isopropoxide complexes, and the like in some cases.

2-5: Sulfonylation

A sulfonamide compound can be obtained by the sulfonylation of an amine compound.

The reaction can be carried out, for example, from under cooling, at room temperature to under heating, by using equivalent amounts of an amine compound and a sulfonyl halide, or an excessive amount of either thereof, in a solvent such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, pyridine, and the like. It may be advantageous for the smooth progress of the reaction to carry out the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine, pyridine, and the like, or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, and the like in some cases.

(Production Processes for Starting Compounds)

The starting material used for the preparation of the compound of the present invention can be prepared, for example, by applying the methods described below, the methods described in Production Examples to be described later, a known method, a method apparent to a skilled person in the art, or a modified method thereof.

(Starting Material Synthesis 1)

Step 1:

A compound (5) can be obtained by reacting a compound (3) with a compound (4).

The reaction can be carried out from at room temperature to under heating, using equivalent amounts of the compound (3) and the compound (4) or an excessive amount of either thereof, in a solvent such as ethers, halogenated hydrocarbons, aromatic hydrocarbons, and the like.

Step 2:

When R³ is —H, a compound (6) in which the substituents at the 3- and 4-positions are trans can be obtained by isomerizing the compound (5).

The reaction can be carried out by treating the compound (5) with a base such as sodium hydroxide, potassium hydroxide, and the like, from at room temperature to under heating, in a solvent such as halogenated hydrocarbons, alcohols, water, and the like.

(Starting Material Synthesis 2)

The compound (3) can be obtained by carrying out dehydration-condensation of a compound (7) with a compound (8).

The reaction can be carried out from at room temperature to under heating, using equivalent amounts of the compound (7) and the compound (8) or an excessive amount of either thereof, in a solvent such as halogenated hydrocarbons, aromatic hydrocarbons, and the like. It may be advantageous for the smooth progress of the reaction to use a dehydrating agent such as anhydrous sodium sulfate, anhydrous magnesium sulfate, Molecular Sieves, and the like in some cases.

(Starting Material Synthesis 3)

Step 1:

A compound (10) can be obtained by reacting a compound (9) with a nitrite.

The reaction can be carried out from under cooling, at room temperature to under heating in a solvent such as ethers, halogenated hydrocarbons, alcohols, and the like in the presence of a nitrite such as ethyl nitrite, butyl nitrite, isoamyl nitrite, and the like. According to the compounds, it is advantageous for the progress of the reaction to carry out the reaction in the presence of an acid such as acetic acid, hydrochloric acid, and the like, or a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, and the like in some cases.

Step 2

A compound (11) can be prepared by subjecting the compound (10) to rearrangement and then to hydrolysis.

The rearrangement reaction can be carried out by treating the compound (10) with thionyl chloride, or the like under cooling.

The hydrolysis reaction can be carried out from at room temperature to under heating, in a solvent such as alcohols, water, and the like, using a base such as sodium hydroxide, potassium hydroxide, and the like.

Step 3

The compound (4) can be obtained by the dehydration of the compound (11).

The dehydration reaction can be carried out from at room temperature to under heating, using acetyl chloride or the like as a dehydrating agent.

The compound of the present invention is isolated and purified as a free compound, a pharmaceutically acceptable salt, hydrate, solvate, or polymorphism thereof. The pharmaceutically acceptable salt of the compound (I) of the present invention can be prepared by a salt formation reaction within a conventional technology.

The isolation and purification can be carried out by employing general chemical operations such as extraction, fractional crystallization, various types of fractional chromatography, and the like.

Various isomers can be separated by selecting an appropriate starting compound, or by making use of the difference in the physicochemical properties between isomers. For example, the optical isomer can be derived into a stereochemically pure isomer by means of general optical resolution methods (for example, fractional crystallization for inducing to diastereomeric salts with optically active bases or acids, chromatography using a chiral column, etc., and the like). In addition, the isomers can also be prepared from an appropriate optically active starting compound.

The pharmacological activity of the compound of the present invention was confirmed by the following test.

Test Example 1 BB2 Receptor Antagonistic Activity

A BB2 receptor binding test was carried out using a membrane sample prepared from a human prostate cancer-derived PC-3 cell. The PC-3 cell was cultured using an RPMI-1640 medium containing 5% fetal bovine serum, and then a membrane sample was prepared by the following methods. The cells detached by a trypsin treatment were added with a 50 mM Tris-HCl buffer (pH 7.4, containing 0.2 mg/ml trypsin inhibitor and 0.2 mg/ml benzamidine), and homogenized by Polytron. The cell suspension was centrifuged at 1,500 rpm for 10 minutes, and the supernatant thus obtained was subjected to 1 hour of ultracentrifugation at 37,000 rpm. The precipitate was suspended in the aforementioned buffer to a concentration of 0.4 mg protein/ml, and stored at −80° C.

The BB2 receptor binding test was carried out by the following method, and the receptor antagonistic activity of a compound to be tested was calculated. A 50 μl of the membrane sample, 50 μl of an assay buffer (20 mM HEPES-HBSS containing 0.1% bovine serum albumin and 0.1 mg/ml bacitracin, pH 7.4), ¹²⁵I [Tyr⁴] bombesin (0.075 nM) and 2 μl of the compound to be tested dissolved in dimethyl sulfoxide were added to a 96 well assay plate, and incubated at room temperature for 2 hours. Non-specific binding was measured using 1 μM of bombesin. After completion of the incubation, the reaction solution was filtered through a Whatman GF/B filter which had been soaked in 0.5% polyethyleneimine. The radioactivity on the filter was measured using a microplate scintillation counter (Top Count, Perkin-Elmer Co., Ltd.). The 50% binding inhibition concentrations of the representative Example Compounds are shown in Table 12. Further, Ex represents the number of the Example compound.

TABLE 12 Ex IC₅₀ (nM) 61 12.8 62 18.3 236 3.0 542 4.7 560 4.8 589 5.7 631 4.5 700 6.7 701 7.4 709 8.9 712 6.7 856 6.8

Test Example 2 Restraint Stress-Induced Defecation Model

The compound to be tested of the present test was used by dissolving in water for injection containing 20% propylene glycol+20% Tween 80 or a 0.5% MC (methyl cellulose) solution.

Fifteen minutes after oral administration of the compound to be tested to a fed male Wistar rat, the animal was put into a restraint stress cage (KN-468, Natsume Seisakusho Co Ltd.). The number of feces excreted during a period from the restriction commencement to 1 hour thereafter was measured. Normal group was put into a separate cage, and number of feces excreted during 1 hour was measured in the same manner.

The inhibitory rates (%) of the representative Example Compounds when they were orally administered at a dose of 1 mg/kg are shown in Table 13. As a result, it was confirmed that the compound of the present invention exhibited an excellent action to improve the bowel movement symptom.

TABLE 13 Ex Inhibitory Rate (%) 542 40.0 560 62.1 589 73.9 631 53.8 700 69.8 701 41.3 709 41.5 712 55.0 856 61.4

As a result of the test as described above, it was confirmed that the compound of the present invention has a BB2 receptor inhibitory action. From this point, it is obvious that the compound is useful as a therapeutic agent for the diseases associated with the BB2 receptors, in particular, IBS, cancers, functional dyspepsia, diabetic gastroparesis, reflux esophagitis, peptic ulcer, and the like.

The preparation containing one or two or more of the compound (I) of the present invention or a salt thereof as an active ingredient can be prepared in accordance with a generally used method, using a pharmaceutical carrier, an excipient, and the like, which are generally employed in the art.

The administration can be accompanied by any mode of oral administration via tablets, pills, capsules, granules, powders, liquid preparations, or the like; or parenteral administration via injections such as intraarticular, intravenous, or intramuscular injections, suppositories, eye drops, eye ointments, transdermal liquid preparations, ointments, transdermal patches, transmucosal liquid preparations, transmucosal patches, inhalations, and the like.

Regarding the solid composition for oral administration according to the present invention, tablets, powders, granules, or the like are used. In such a solid composition, one or two or more of active ingredients are mixed with at least one inactive excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, and/or magnesium aluminometasilicate, and the like. According to a conventional method, the composition may contain inert additives such as a lubricant such as magnesium stearate, a disintegrator such as carboxymethyl starch sodium, a stabilizing agent, and a solubilizing agent. As necessary, tablets or pills may be coated with a sugar coating, or a film of a gastric or enteric material.

The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, or the like, and contains a generally used inert diluent such as purified water and ethanol. In addition to the inert solvent, this liquid composition may contain an auxiliary agent such as a solubilizing agent, a moistening agent, and a suspending agent, a sweetener, a flavor, an aroma, and an antiseptic.

The injections for parenteral administration include sterile aqueous or non-aqueous liquid preparations, suspensions, and emulsions. As the aqueous solvent, for example, distilled water for injection and physiological saline are included. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, plant oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (Japanese Pharmacopeia), and the like. Such a composition may further contain a tonicity agent, an antiseptic, a moistening agent, an emulsions, a dispersant, a stabilizer, or a solubilizing agent. These are sterilized, for example, by filtration through a bacteria retaining filter, blending of a bactericide, or irradiation. In addition, these can also be used by preparing a sterile solid composition, and dissolving or suspending in sterile water or a sterile solvent for injection prior to its use.

The drug for external use includes ointments, plasters, creams, jellies, cataplasms, sprays, lotions, eye drops, eye ointments, and the like. The drug contains generally used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. Examples of the ointment or lotion bases include polyethylene glycol, propylene glycol, white vaseline, bleached beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, and the like.

Regarding a transmucosal agent such as an inhalation, a transnasal agent, and the like, those in a solid, liquid, or semi-solid state are used, and may be produced in accordance with a conventionally known method. For example, a known excipient, and in addition, a pH adjusting agent, an antiseptic, a surfactant, a lubricant, a stabilizing agent, a thickening agent, and the like may be added thereto, if desired. For their administration, an appropriate device for inhalation or blowing may be used. For example, a compound may be administered alone or as a powder of formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using a conventionally known device or sprayer, such as a measured administration inhalation device and the like. The dry powder inhaler or the like may be for single or multiple administration use, and a dry powder or a powder-containing capsule may be used. Alternatively, this may be in a form such as a high pressurized aerosol spray which uses an appropriate propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, carbon dioxide, and the like.

In the case of conventional oral administration, the daily dose may be generally from about 0.001 to 100 mg/kg, preferably from 0.1 to 30 mg/kg, and even more preferably 0.1 to 10 mg/kg, per body weight, and this is administered in one portion or in 2 to 4 divided portions. Also, in the case of intravenous administration, the daily dose is from about 0.0001 to 10 mg/kg per body weight, once a day or twice or more times a day. In addition, a transmucosal agent is administered at a dose from about 0.001 to 100 mg/kg per body weight, once a day or twice or more times a day. The dose is appropriately decided in response to an individual case by taking symptoms, age, gender, or the like into consideration.

The compound of the present invention can be used in combination with various therapeutic or prophylactic agents for the diseases, for which the compound of the present invention is considered effective. The combined preparation may be administered simultaneously, or separately and continuously or at a desired time interval. The preparations to be co-administered may be a blend, or prepared individually.

Examples

Hereinbelow, the production processes for the compound (I) of the present invention will be described in more detail with reference to Examples. The compound of the present invention is not limited to the compounds described in Examples below. Further, the production processes for the starting compounds will be described in Production Examples.

In addition, the following abbreviations are used in Examples, Production Examples, and Tables to be described later.

PEx: Production Example, Ex: Example, No: Compound No., Data: Physicochemical Data (EI+: m/z value in EI-MS (cation) (unless otherwise mentioned, (M)⁺.), FAB+: m/z value in FAB-MS (cation) (unless otherwise mentioned, (M+H)⁺.), FAB−: m/z value in FAB-MS (anion) (unless otherwise mentioned, (M−H)⁻.), ESI+: m/z value in ESI-MS (cation) (unless otherwise mentioned, (M+H)⁺.), ESI−: m/z value in ESI-MS (anion) (unless otherwise mentioned, (M−H)⁻.), CI+: m/z value in CI-MS (cation) (unless otherwise mentioned, (M+H)⁺.), APCI+: m/z value in APCI-MS (cation) (unless otherwise mentioned, (M+H)⁺.), APCI−: m/z value in APCI-MS (anion) (unless otherwise mentioned, (M+H)⁺.), NMR1: δ (ppm) of characteristic peak in δ (ppm) by ¹H-NMR in DMSO-d₆), Structure: Structural Formula (a case where HCl, HBr, fum, or TFA is described in the structural formula indicates that the compound is hydrochloride, hydrobromide, fumarate, or trifluoroacetate, respectively. In the case where a numeral is attached before a salt component, the numeral means a molar ratio of the compound to the salt component. For example, a case where 2HCl is described means that the compound is dihydrochloride. Further, a case where H₂O is described in the structural formula indicates that the compound is a hydrate in each case.), Syn: Production Process (the numeral shows that it was prepared using a corresponding starting material, similar to the case of an Example Compound having its number as the Example No.). In the case where P is attached before the numeral, the number shows that it was produced using a corresponding starting material, similar to the case of a Production Example Compound having its number as the Prosuction Example No. A case where a plurality of the numerals is described indicates that the compound was prepared by carrying out the reaction in order starting from the front numeral, using a corresponding starting material. Note: (the racemic mixture means a racemic mixture, the diastereo mixture means a diastero mixture, and the chiral compound means a chiral compound, in which a part of its stereochemistry is not clear. Further, less polar and more polar mean a low polarity product and a high polarity product, respectively, as compared with the corresponding diastereomers, in thin layer chromatography. Further, 3,4-trans, 1′,2′-cis, and the like mean the relative configurations of the substituents or the like. Provided that the numeral which is not dashed means the position substituted in the tetrahydroisoquinolin-1-one ring, and the dashed numeral means the position substituted in the substituent at the 2-position in a tetrahydroisoquinolin-1-one ring. For example, 3,4-trans indicates that the substituents at the 3- and 4-positions in the tetrahydroisoquinolin-1-one ring are trans.) Boc: a tert-butoxycarbonyl group, DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene.

In addition,

indicates that the double bond is cis or trans, or a mixture thereof.

Production Example 1

10 g of 5-(benzyloxy)-1H-indene-1,2(3H)-dione 2-oxime was added to 20 ml of thionyl chloride at 0° C., followed by stirring for 20 minutes under the same condition. After warming to room temperature, thionyl chloride was evaporated under reduced pressure. To the residue was added 20 ml of a 40% aqueous potassium hydroxide solution, followed by heating under reflux overnight. After cooling to room temperature, and neutralizing by the addition of concentrated hydrochloric acid, the precipitated solid was collected by filtration to obtain 9.9 g of 4-(benzyloxy)-2-(carboxymethyl)benzoic acid as a dark brown powder.

Production Example 2

To a mixture of 2.01 g of diethyl [3-(1,3-dioxolan-2-yl)phenyl]malonate, 2.89 g of calcium chloride, and 50 m of ethanol was added 2.47 g of sodium borohydride under ice-cooling, followed by stirring at the same temperature for 2 hours and at room temperature for 4 hours. To the reaction solution was added 10 ml of water at room temperature, followed by stirring for 30 minutes. The insoluble material was separated by filtration using Celite, and the filtrate was concentrated under reduced pressure to obtain 0.76 g of 2-[3-(1,3-dioxolan-2-yl)phenyl]propane-1,3-diol as a colorless oily substance.

Production Example 3

A mixture of 1.83 g of 2-[3-(1,3-dioxolan-2-yl)phenyl]propane-1,3-diyl diacetate and 60 ml of a 83% aqueous acetic acid solution was stirred at 50° C. for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 1.59 g of 2-(3-formylphenyl)propane-1,3-diyl diacetate as a colorless oily substance.

Production Example 4

To a solution of 958 mg of (6-methylpyridin-3-yl)methanol, 1.3 ml of triethylamine, and 95 mg of DMAP in 40 ml of dichloromethane was added dropwise 1.08 ml of benzoyl chloride, followed by stirring at room temperature. To the reaction solution was added water, followed by carrying out an extraction operation with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 1767 mg of (6-methylpyridin-3-yl)methyl benzoate.

Production Example 5

To a solution of 1767 mg of (6-methylpyridin-3-yl)methyl benzoate in 26.5 ml of chloroform was added 2440 mg of m-chloroperbenzoic acid under ice-cooling, followed by stirring for 1 hour. An aqueous potassium carbonate solution was added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure to obtain 1891 mg of (6-methyl-1-oxidopyridin-3-yl)methyl benzoate.

Production Example 6

To a solution of 1891 mg of (6-methyl-1-oxidopyridin-3-yl)methyl benzoate in 38 ml of DMF was added 11 ml of trifluoroacetic anhydride, followed by stirring at room temperature overnight. After evaporating trifluoroacetic anhydride under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 3.675 g of [6-(hydroxymethyl)pyridin-3-yl]methyl benzoate.

Production Example 7

To a solution of 858 mg of pyrazine-2,5-diyl bis(methylene) diacetate in 8.6 ml of methanol was added 600 mg of zeolite, followed by heating under reflux for 4 days. Zeolite was removed by filtration and then concentrated, and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 209 mg of [5-(hydroxymethyl)pyrazine-2-yl]methyl acetate.

Production Example 8

To a mixture of 313 mg of 6-(hydroxymethyl)nicotinamide, 540 mg of triphenylphosphine, 503 mg of N-hydroxyphthalimide, and 4.7 ml of THF was added dropwise 0.53 ml of diisopropyl azodicarboxylate, followed by stirring overnight. After concentration, the solid thus produced was suspended in water, and ethyl acetate was added thereto. After stirring for 30 minutes, the solid was collected by filtration to obtain 292 mg of 6-{[(1,3-dioxo-1,3-dihydro-2H-isoindo1-2-yl)oxy]methyl}nicotinamide.

Production Example 9

To a suspension of 292 mg of 6-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}nicotinamide in 4.4 ml of methanol was added 0.2 ml of a 40% methyl amine/methanol solution, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated, ethyl acetate was added thereto, and the precipitated crystal was separated by filtration and then concentrated under reduced pressure to obtain 146 mg of 6-[(aminooxy)methyl]nicotinamide.

Production Example 10

To a mixture of 3.0 g of 6-chloronicotinic acid and 111 ml of THF was added 6.4 g of potassium tert-butoxide, followed by heating under reflux for 1 day. The reaction solution was poured into water, neutralized with citric acid, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 2.16 g of 6-tert-butoxynicotinic acid.

Production Example 11

To a mixed liquid of 2163 mg of 6-tert-butoxynicotinic acid and 32 ml of acetone were added 2297 mg of potassium carbonate and 0.97 ml of methyl iodide, followed by stirring at 35° C. overnight. Ethyl acetate and water were added thereto to carry out liquid separation, and the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 1.191 g of methyl 6-tert-butoxynicotinate.

Production Example 12

To a mixed liquid of 1191 mg of methyl 6-tert-butoxynicotinate and 35.7 ml of ethanol was slowly added 2153 mg of sodium borohydride, followed by stirring at 50° C. for 18 hours. After the addition of methanol, water and ethyl acetate were added thereto to carry out an extraction operation. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 0.949 g of (6-tert-butoxypyridin-3-yl)methanol.

Production Example 13

To a mixed liquid of 1020 mg of 5-[(aminooxy)methyl]-2-tert-butoxypyridine, which had been obtained by reacting (6-tert-butoxypyridin-3-yl)methanol and N-hydroxyphthalimide in accordance with Production Example 8, and then carrying out the removal of phthalimide in accordance with Production Example 9, and 20 ml of ethyl acetate was added 1.3 ml of concentrated hydrochloric acid under ice-cooling, followed by stirring for 30 minutes. The resulting solid was separated by filtration, concentrated hydrochloric acid was further added to the filtrate, and the precipitated solid was collected by filtration to obtain 351 mg of 5-[(aminooxy)methyl]pyridin-2(1H)-one hydrochloride as a colorless solid.

Production Example 14

To a mixture of 659 mg of 1-(chloromethyl)-4-(methylsulfonyl)benzene and 10 ml of DMSO were added 525 mg of N-hydroxyphthalimide and 445 mg of potassium carbonate, followed by stirring at 50° C. for 2 hours. The reaction solution was cooled, water was then added thereto, and the precipitated crystal was collected by filtration to obtain 685 mg of 2-{[4-(methylsulfonyl)benzyl]oxy}-1H-isoindole-1,3(2H)-dione as a white solid.

Production Example 15

To a solution of 5.08 g of tert-butyl [4-(hydroxymethyl)phenoxy]acetate and 4.6 ml of triethylamine in 30 ml of dichloromethane was added 1.98 ml of methanesulfonyl chloride under ice-cooling, followed by stirring for 1 hour under ice-cooling. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. To a solution of the obtained residue in 40 ml of DMF was added 4.26 g of sodium azide, followed by stirring at 60° C. for 15 hours. After leaving it to be cooled, the reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to obtain 5.16 g of tert-butyl [3-(azidomethyl)phenoxy]acetate as a pale yellow oily substance.

Production Example 16

To a mixed liquid of 5.00 g of methyl 5-formylthiophene-3-carboxylate and 50 ml of THF was added 0.67 g of sodium borohydride under ice-cooling. To the reaction solution was added dropwise 5 ml of methanol, followed by stirring for 1 hour under ice-cooling. The reaction solution was added with 1 M hydrochloric acid, extracted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated to obtain 4.86 g of methyl 5-(hydroxymethyl)thiophene-3-carboxylate as a pale yellow oily substance.

Production Example 17

To a mixed liquid of 4.86 g of methyl 5-(hydroxymethyl)thiophene-3-carboxylate and 50 ml of dichloromethane was added 4.12 ml of thionyl chloride under ice-cooling, followed by stirring at room temperature for 15 hours. The reaction solution was concentrated, added with ethyl acetate, and then washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was then evaporated to obtain 4.90 g of methyl 5-(chloromethyl)thiophene-3-carboxylate as a pale yellow oily substance.

Production Example 18

To a solution of 3.69 g of di-tert-butyl imidodicarbonate in 54 ml of DMF was added 1.91 g of potassium tert-butoxide at 0° C. under argon, followed by stirring at room temperature for 1 hour. A solution of 2.7 g of methyl 5-(chloromethyl)thiophene-3-carboxylate in 8.1 ml of DMF was slowly added thereto, followed by stirring at room temperature overnight. Water and ethyl acetate were added to the reaction solution, followed by carrying out an extraction operation, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 4.394 g of methyl 5-{[bis(tert-butoxycarbonyl)amino]methyl}thiophene-3-carboxylate.

Production Example 19

To a mixed liquid of 400 mg of ethyl difluoro(3-methylphenyl) acetate and 10 ml of carbon tetrachloride were added 349 mg of N-bromosuccinimide and 15 mg of 2,2′-azobis(isobutyronitrile), followed by heating under reflux for 2 hours. After cooling the reaction solution, the insoluble material was separated by filtration, and the filtrate was concentrated. The residue was added with hexane, washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 458 mg of ethyl [3-(bromomethyl)phenyl](difluoro) acetate as a colorless oily substance.

Production Example 20

To a mixed liquid of 2.89 g of ethyl 2-methyl-2-(3-methylphenyl)propionate and 90 ml of carbon tetrachloride were added 4.98 g of N-bromosuccinimide and 115 mg of 2,2′-azobis(isobutyronitrile), followed by stirring at 80° C. for 2 hours, and 4.98 g of N-bromosuccinimide and 115 mg of 2,2′-azobis(isobutyronitrile) were further added thereto, followed by stirring at 80° C. for 14 hours. After cooling the reaction solution, the insoluble material was separated by filtration, and the solvent was evaporated. To the residue was added hexane and followed by washing with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated to obtain 6.0 g of a pale yellow oily substance. The obtained oily substance was dissolved in 30 ml of THF, and 21.7 ml of diethyl phosphite and 29.3 ml of diisopropylethylamine were added thereto under ice-cooling, followed by stirring at room temperature for 13 hours. The reaction solution was poured into ice water, followed by extraction with hexane. The organic layer was washed with 1 M hydrochloric acid and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 2.95 g of ethyl 2-[3-(dibromomethyl)phenyl]-2-methylpropionate as a pale yellow oily substance.

Production Example 21

To a mixed liquid of 2.95 g of ethyl 2-[3-(dibromomethyl)phenyl]-2-methylpropionate and 30 ml of acetic acid was added 4.77 g of potassium acetate, followed by stirring at 100° C. for 6 hours. After cooling the reaction solution, 10 ml of 6 M hydrochloric acid was added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was poured into water, followed by extraction with hexane, and the organic layer was washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated to obtain 1.74 g of ethyl 2-(3-formylphenyl)-2-methylpropionate as a colorless oily substance.

Production Example 22

To a mixed liquid of 1.00 g of tert-butyl piperidin-4-ylcarbamate and 20 ml of pyridine was added 0.77 ml of methanesulfonyl chloride, followed by stirring at room temperature for 18 hours. After evaporating the pyridine under reduced pressure, ethyl acetate was added thereto, followed by washing with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated, and the obtained solid was washed with diethyl ether to obtain 1.19 g of t-butyl[1-(methylsulfonyl)piperidin-4-yl]carbamate as a white solid.

Production Example 23

To a solution of 1 g of tert-butyl [3-(cyanomethyl)phenoxy]acetate in 20 ml of THF and 10 ml of methanol was added dropwise a suspension of 1.31 g of cobalt chloride and 20 ml of water, and then 459 mg of sodium borohydride was portionwise added thereto at room temperature. After stirring at room temperature for 10 minutes, the insoluble material was separated by filtration over Celite, washed with methanol, and then concentrated. The obtained residue was extracted with chloroform, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol-saturated aqueous ammonia) to obtain 632 mg of tert-butyl [3-(2-aminoethyl)phenoxy]acetate as a pale yellow oily substance.

Production Example 24

To a mixed liquid of 5.16 g of t-butyl [3-(azidomethyl)phenoxy]acetate and 50 ml of THF were added 6.17 g of triphenylphosphine and 1.04 ml of water, followed by stirring at room temperature for 4 days. The solvent was evaporated and diisopropyl ether was added thereto. The precipitated solid was separated by filtration and the solvent was evaporated again. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol-saturated aqueous ammonia) to obtain 4.10 g of t-butyl[3-(aminomethyl)phenoxy]acetate as a pale yellow oily substance.

Production Example 25

To a mixed liquid of 2.00 g of (1RS,2SR)-2-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid and 40 ml of dichloromethane were added 1.41 ml of 2-(trimethylsilyl)ethanol, 0.40 g of DMAP, and 2.21 g of WSC in this order, followed by stirring at room temperature for 60 hours. After evaporating the solvent, ethyl acetate was added thereto, followed by washing with water, a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated to obtain 2.82 g of 2-(trimethylsilyl)ethyl(1RS,2SR)-2-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate as a colorless oily substance.

Production Example 26

To a solution of 2.82 g of 2-(trimethylsilyl)ethyl(1RS,2SR)-2-[(t-butoxycarbonyl)amino]cyclohexanecarboxylate in 10 ml of ethyl acetate, were added 20 ml of 4 M hydrogen chloride/ethyl acetate under ice-cooling, followed by stirring at room temperature for 6 hours. The reaction solution was evaporated to obtain 2.30 g of 2-(trimethylsilyl)ethyl(1RS,2SR)-2-aminocyclohexanecarboxylate as a colorless amorphous substance.

Production Example 27

To a mixed liquid of 4.40 g of N-[(benzyloxy)carbonyl]-3-[(methylsulfonyl)amino]-D-alanine methyl ester, 100 ml of THF, and 50 ml of ethanol was added 1.13 g of lithium chloride, and 1.01 g of sodium borohydride was further added thereto under ice-cooling. The reaction solution was stirred at room temperature for 14 hours, and the solvent was then evaporated under reduced pressure. After adding 150 ml of water, concentrated hydrochloric acid was added thereto until the pH reached 2 to 3. The solution was extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain 3.10 g of benzyl[(1R)-2-hydroxy-1-{[(methylsulfonyl)amino]methyl}ethyl]carbamate as a white solid.

Production Example 28

To a mixed liquid of 3.10 g of benzyl[(1R)-2-hydroxy-1-{[(methylsulfonyl)amino]methyl}ethyl]carbamate and 50 ml of ethanol was added 500 mg of 5% palladium/carbon, followed by stirring at room temperature for 2 hours under a hydrogen atmosphere. The palladium/carbon was separated by filtration and the solvent was then evaporated to obtain 1.72 g of N-[(2R)-2-amino-3-hydroxypropyl]methanesulfonamide as a colorless oily substance.

Production Example 29

To 700 mg of 2-(6-methoxypyridin-2-yl)ethylamine was added 10 ml of a 47% aqueous hydrogen bromide solution, followed by stirring at 80° C. for 60 hours. After evaporating the solvent, the residue was washed with diethyl ether to obtain 1.21 g of a 6-(2-aminoethyl)pyridin-2(1H)-one hydrobromide as a pale brown solid.

Production Example 30

A mixture of 3980 mg of 2-[2-(1H-tetrazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione, 0.90 g of hydrazine monohydrate, and 80 ml of ethanol was stirred at 70° C. for 12 hours. The reaction solution was left to be cooled and the insoluble material was then collected by filtration. The filtered material was suspended in dioxane and 3.57 g of di-tert-butyl dicarbonate was added thereto at room temperature, followed by stirring for 12 hours. The insoluble material was separated by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using hexane/ethyl acetate as an eluent solvent to obtain 2210 mg of tert-butyl[2-(1H-tetrazol-1-yl)ethyl]carbamate as a colorless solid.

Production Example 31

To a solution of 2.62 g of tert-butyl 1H-pyrrole-3-carboxylate and 7.96 g of N-(2-bromoethyl)phthalimide in DMF (100 ml) was added 10.2 g of cesium carbonate at room temperature, followed by stirring for 12 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using hexane/chloroform as an eluent solvent, and washed with diethyl ether to obtain 670 mg of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindo1-2-yl)ethyl]-1H-pyrrole-3-carboxylate as a colorless solid.

Production Example 32

A mixture of 660 mg of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1H-pyrrole-3-carboxylate, 194 mg of hydrazine monohydrate, and 19 ml of ethanol was stirred at 70° C. for 12 hours. The reaction solution was left to be cooled and the insoluble material was then separated by filtration. The filtrate was concentrated under reduced pressure to obtain 430 mg of tert-butyl 1-(2-aminoethyl)-1H-pyrrole-3-carboxylate as a yellow oily substance.

Production Example 33

To a solution of 8.75 g of 2,4-dichlorobenzaldehyde in 100 ml of chloroform were added 5.11 g of cyclopentylamine and 5 g of Molecular Sieves 4A, followed by stirring at room temperature overnight. After removing the Molecular Sieves 4A by filtration, 6.48 g of homophthalic anhydride was added thereto, followed by stirring at room temperature overnight and then reflux for 5 hours. After concentrating under reduced pressure, ethyl acetate and a 1 M aqueous sodium hydroxide solution were added thereto to carry out a liquid separation operation. The aqueous layer was acidified by the addition of 1 M hydrochloric acid, followed by extraction with chloroform-isopropyl alcohol (3:1). The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was added with ether and collected by filtration to obtain 4.48 g of 3,4-cis-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Production Example 33-1) as a colorless crystal. The mother liquid was concentrated to obtain 6.46 g of 3,4-trans-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Production Example 33-2) as a colorless amorphous substance.

Production Example 34

To a mixed solution of 2,4-dichlorobenzaldehyde in chloroform-methanol were added trans-2-aminocyclohexanol, triethylamine, and anhydrous sodium sulfate at room temperature, the reaction solution was stirred at 50° C. overnight, and homophthalic anhydride was then added thereto at room temperature, followed by stirring at room temperature overnight. After removing sodium sulfate by filtration, chloroform and a 1 M aqueous sodium hydroxide solution were added thereto to carry out a liquid separation operation, and the aqueous layer was stirred at room temperature for 2 hours. It was acidified by the addition of 1 M hydrochloric acid, and ethyl acetate was added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. To the residue was added diethyl ether, followed by stirring at room temperature overnight. The precipitated crystal was collected by filtration to obtain 7655 mg of 3RS,4RS-3-(2,4-dichlorophenyl)-2-(1SR,2SR-2-hydroxycyclohexyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Production Example 34-1) as a colorless crystal. After concentrating the mother liquid, the residue was purified by silica gel column chromatography (eluent: chloroform:methanol) to obtain 6600 mg of 3SR,4SR-3-(2,4-dichlorophenyl)-2-(1RS,2RS-2-hydroxycyclohexyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Production Example 34-2) as a colorless crystal.

Production Example 35

To 4.33 g of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid were added 50 ml of ethanol and 2 ml of concentrated sulfuric acid, followed by heating under reflux overnight. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 2.3 g of ethyl (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate as a yellow foam.

Production Example 36

To a solution of 2.25 g of ethyl (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate in 30 ml of acetonitrile were added 0.75 ml of methanesulfonyl chloride and 1.6 ml of diisopropylethylamine, followed by stirring at room temperature overnight. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was added with diethyl ether for crystallization, and collected by filtration to obtain 2.02 g of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate as a colorless crystal.

Production Example 37

To a solution of 1.4 g of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate in 20 ml of DMF was added 229 mg of sodium hydride under ice-cooling, followed by stirring at the same temperature for 10 minutes, and then 0.17 ml of methyl iodide was added thereto, followed by stirring under ice-cooling for 30 minutes. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 545 mg of ethyl (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[methyl(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate as a colorless amorphous substance.

Production Example 38

To a mixture of 2.0 g of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate, 10 ml of methanol, and 10 ml of THF was added 10 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 1 hour. The solution was acidified by the addition of 1 M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 1.9 g of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid as a pale yellow crystal.

Production Example 39

A mixture of 8 g of 4-(benzyloxy)-2-(carboxymethyl)benzoic acid and 30 ml of acetyl chloride was heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, added with ether, and collected by filtration to obtain 7.50 g of 6-(benzyloxy)-1H-isochromene-1,3(4H)-dione as a dark brown solid.

Production Example 40

To 612 mg of 6-[(aminooxy)methyl]pyridin-2(1H)-one, which had been prepared by subjecting 2-[(6-oxo-1,6-dihydropyridin-2-yl)methoxy-1H-isoindole-1,3(2H)dione to removal of phthalimide in accordance with Production Example 9, was added 1.6 ml of a 4 M hydrogen chloride/ethyl acetate solution, and the precipitated solid was collected by filtration to obtain 263 mg of 6-[(aminooxy)methyl]pyridin-2(1H)-one hydrochloride as a colorless solid.

Production Example 41

To 2.04 g of (4-methyl-1H-imidazol-5-yl)methanol hydrochloride was added 20 ml of acetonitrile, and 2.1 ml of triethylamine, 3.14 g of di-tert-butyl dicarbonate, and 0.17 g of DMAP were added thereto under ice-cooling, followed by stirring at room temperature. After concentrating the reaction solution under reduced pressure, ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The obtained residue was reacted with N-hydroxyphthalimide in accordance with Production Example 14, reacted with methylamine in accordance with Production Example 9, and then subjected to deprotection of a Boc group in accordance with Production Example 26 to obtain 0.53 g of 5-[(aminooxy)methyl]-4-methyl-1H-imidazole dihydrochloride as a colorless solid.

Production Example 42

To a solution of 529 mg of (5-fluoropyridin-2-yl)methanol and 0.64 ml of triethylamine in 8 ml of dichloromethane was added 0.35 ml of methanesulfonyl chloride under ice-cooling, followed by stirring for 1 hour under ice-cooling. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The obtained residue was reacted with N-hydroxyphthalimide in accordance with Production Example 14 to obtain 522 mg of 2-[(5-fluoropyridin-2-yl)methoxy]-1H-isoindole-1,3(2H)-dione as a white solid.

Production Example 43

To a mixture of 2.97 g of 4-(hydroxymethyl)phenol, 4.90 g of tert-butyl bromoacetate, and 25 ml of DMF was added 4.96 g of potassium carbonate at room temperature, followed by stirring for 12 hours. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to obtain a pale yellow oily substance. This oily substance was subjected to methanesulfonylation in accordance with Production Example 15, and then reacted with sodium azide to obtain 4.03 g of tert-butyl[4-(azidomethyl)phenoxy]acetate as a pale yellow oily substance.

Production Example 44

To a solution of 1.63 g of ethyl(3RS,4RS)-2-[(1SR,2SR)-2-{[(3-chloropropyl)sulfonyl]amino}cyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate in 20 ml of THF was added 142 mg of sodium hydride, followed by stirring at 50° C. overnight. Ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 466 mg of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(1,1-dioxidoisothiazolidin-2-yl)cyclohexyl]-1-oxo-tetrahydroisoquinoline-4-carboxylate as a colorless crystal.

Production Example 45

A solution of 5.0 g of 4-bromothiophene-2-carbaldehyde, 11.4 ml of vinyltributyltin, and 3.6 g of tetrakistriphenylphosphine palladium in 100 ml of toluene was overheated at 110° C. for 4 hours under a sealed tube condition. The organic layer was extracted with ethyl acetate and washed with water. In addition, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 3.4 g of 4-vinylthiophene-2-carbaldehyde as a brown liquid.

Production Example 46

A solution of 5 g of methyl 1-methyl-1H-imidazole-5-carboxylate and 22.5 g of paraformaldehyde in 50 ml of methanol was overheated at 140° C. for 60 hours under a sealed tube condition. The precipitate was removed by filtration and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 4 g of methyl 2-(hydroxymethyl)-1-methyl-1H-imidazole-5-carboxylate as a white solid.

Production Example 47

7.4 ml of phosphorous oxychloride was added dropwise to 8.1 ml of DMF at 0° C., followed by warming to room temperature. To the solution was added ethyl 3-furanate, followed by warming to 126° C. and stirring for 1 hour. After cooling to room temperature, the reaction solution was poured into ice water. The organic layer was extracted with diethyl ether and washed with a saturated aqueous sodium carbonate solution. In addition, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 850 mg of ethyl 5-formyl-3-furnate as a yellow solid.

Production Example 48

To a mixed liquid of 1.51 g of potassium cyanide and 70 ml of acetonitrile, 6.12 g of 1,4,7,10,13,16-hexaoxacyclooctadecane was added, followed by stirring for 2 hours. Thereafter, a solution of 5.00 g of tert-butyl 3-(chloromethyl)benzoate in 30 ml of acetonitrile was added thereto, followed by stirring at room temperature for 18 hours. The reaction solution was concentrated, diluted with diethyl ether-hexane (1:1), and then washed with water and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 3.86 g of tert-butyl 3-(cyanomethyl)benzoate as a colorless oily substance.

Production Example 49

A solution of 2 g of (benzyloxy)acetic acid in 30 ml of DMF was cooled to 0° C., and 2.44 g of 1-(4-aminophenyl)ethanone, 294 mg of DMAP, and 3.73 g of WSC/hydrochloride were added thereto, followed by stirring at room temperature for 3 hours. Liquid separation was carried out with ethyl acetate-1 M hydrochloric acid. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 3.12 g of N-(4-acetylphenyl)-2-(benzyloxy)acetamide.

Production Example 50

To a solution of 1.64 g of ethyl 2-(hydroxymethyl)isonicotinate in 32.8 ml of dichloromethane were added 1.24 ml of dihydropyrane and 2.32 g of pyridinium p-toluenesulfonate, followed by stirring overnight. Ethyl acetate was added thereto, followed by washing with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 2.4 g of ethyl 2-[(tetrahydro-2H-pyran-2-yloxy)methyl]isonicotinate.

Production Example 51

To a solution of 1.8 g of 1-[6-(hydroxymethyl)pyridin-2-yl]ethanone oxime in 36 ml of methanol was added 500 mg of 10% palladium-carbon (50% wet) under an argon atmosphere, followed by stirring for 7 hours under a hydrogen gas flow. After filtration through Celite, the filtrate was evaporated under reduced pressure to obtain 1.5 g of [6-(1-aminoethyl)pyridin-2-yl]methanol.

Production Example 52

To a solution of 2.06 g of 3-amino-4-hydroxybenzoic acid in 20.6 ml of THF was added 4.81 g of CDI, followed by stirring at room temperature for 1 hour. The reaction mixture was added dropwise to a mixed liquid of 3.06 g of sodium borohydride in 20.6 ml of THF and 8.26 ml of water, cooled to 0° C., which had been separately prepared, followed by stirring overnight. 1 M hydrochloric acid was added thereto, followed by extracting with ethyl acetate, and washing with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 1.2 g of 5-(hydroxymethyl)-1,3-benzoxazol-2(3H)-one.

Production Example 53

To 5 g of diethylpyridine-2,4-dicarboxylate were added 50 ml of ethanol and 50 ml of dichloroethane, followed by ice-cooling. 932 mg of sodium borohydride was added portionwise thereto, followed by stirring for 1 hour under ice-cooling, and further at room temperature for 15 hours. After ice-cooling the reaction solution, 5 ml of 6 M hydrochloric acid was added thereto, followed by stirring for 5 minutes and concentrating. A saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extracting with chloroform-isopropanol (10:1) and drying over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 0.7 g of ethyl 4-(hydroxymethyl)pyridine-2-carboxylate (Production Example 53-1) and 1.6 g of ethyl 2-(hydroxymethyl)isonicotinate (Production Example 53-2), respectively.

Production Example 54

To 1.6 g of 1-(6-methoxypyridin-2-yl)ethanamine was added 23.7 ml of a 47% aqueous hydrobromic acid solution, followed by stirring at 80° C. for 60 hours. After evaporating the solvent under reduced pressure, the residue was washed with diethyl ether to obtain 2.95 g of 6-(1-aminoethyl)pyridin-2(1H)-one hydrobromide as a pale brown solid.

Production Example 55

To a solution of 2.31 g of tert-butyl 1H-pyrazole-3-carboxylate and 6.98 g of N-(2-bromoethyl)phthalimide in DMF (65 mL) was added 8.95 g of cesium carbonate at room temperature, followed by stirring for 12 hours. The reaction solution was diluted with water, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-hexane) to obtain 1.51 g of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1H-pyrazole-3-carboxylate as a colorless solid.

Production Example 56

To a mixture of 2.92 g of (2-hydroxyphenyl)acetonitrile, 4.71 g of tert-butyl bromoacetate and 110 mL of DMF was added 6.06 g of potassium carbonate at room temperature, followed by stirring for 12 hours. To the reaction solution was added water, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using hexane/ethyl acetate as an eluent solvent to obtain 5.29 g of tert-butyl[2-(cyanomethyl)phenoxy]acetate as a yellow oily substance.

Production Example 57

A mixture of 1.38 g of 6-(hydroxymethyl)pyridin-2(1H)-one, 2.15 g of tert-butyl bromoacetate, 3.07 g of silver oxide, and 33 mL of DMF was stirred at room temperature for 12 hours, and then at 60° C. for 12 hours. The insoluble material was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, followed by washing with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 1.92 g of tert-butyl{[6-(hydroxymethyl)pyridin-2-yl]oxy}acetate as a yellow oily substance.

Production Example 58

To a mixture of 1.00 g of 3-hydroxybenzaldehyde, 1.80 g of tert-butyl(R)-lactate, 2.58 g of triphenylphosphine, and 40 mL of THF was added 1.71 g of diethyl azodicarboxylate at room temperature, followed by stirring for 12 hours. The reaction solution was diluted with ethyl acetate, followed by washing with a 5% aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 1.49 g of tert-butyl(2S)-2-(3-formylphenoxy)propanoate as a colorless oily substance.

To a solution of 1.48 g of tert-butyl(2S)-2-(3-formylphenoxy)propanoate in methanol (30 mL) was added 0.48 g of sodium borohydride under ice-cooling, followed by stirring for 1 hour. The reaction solution was diluted with ethyl acetate, added with water, neutralized with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 1.38 g of tert-butyl(2S)-2-[3-(hydroxymethyl)phenoxy]propanoate as a colorless oily substance.

Production Example 59

A solution of 2.90 g of 1,3-phenylene diacetic acid, 3.00 g of 4-methoxybenzylbromide, and 2.99 g of potassium hydrogen carbonate in 15 mL of DMF was stirred at room temperature for 36 hours. To the reaction solution was added water, followed by neutralization with 1 M hydrochloric acid. The product was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, 4.72 g of a colorless oily substance was obtained. A mixture of the obtained colorless oily substance (4.72 g), 2.42 g of HOBt, 2.78 g of WSC hydrochloride, 3.99 g of ammonium chloride, 7.55 g of triethylamine, and 18 mL of DMF was stirred at room temperature for 12 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 4-methoxybenzyl[3-(2-amino-2-oxoethyl)phenyl]acetate as a colorless solid.

To a solution of 1.31 g of 4-methoxybenzyl[3-(2-amino-2-oxoethyl)phenyl]acetate in pyridine (20 mL) was added 718 mg of methanesulfonyl chloride under ice-cooling, followed by stirring for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with a 5% aqueous citric acid solution, a 5% saturated aqueous sodium hydrogen carbonate solution, and then a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 1.25 g of 4-methoxybenzyl[3-(cyanomethyl)phenyl]acetate as a yellow oily substance.

Production Example 60

A mixture of 5.05 g of 5-methyl-2-furanecarboxylic acid, 7.14 g of CDI, and 40 mL of DMF was stirred at 50° C. for 2 hours. To the reaction solution were added 6.71 g of DBU and 6.53 g of 2-methyl-2-propanol at room temperature, followed by stirring at 50° C. for 48 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with diethyl ether and washed with a 5% aqueous ammonium chloride solution, a 5% saturated aqueous sodium hydrogen carbonate solution, and then a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 2.82 g of tert-butyl 5-methyl-2-furanecarboxylate as a yellow oily substance.

Production Example 61

To a solution of 1643 mg of 1-[6-(hydroxymethyl)pyridin-2-yl]ethanone in 25 ml of ethanol was added 0.72 ml of a 50% aqueous hydroxylamine solution, followed by stirring overnight. The reaction solution was concentrated under reduced pressure to obtain 1806 mg of 1-[6-(hydroxymethyl)pyridin-2-yl]ethanone oxime as an amorphous substance.

Production Example 62

To a mixture of 2.06 g of tert-butyl({6-[(hydroxymethyl)pyridin-2-yl]oxy}acetate, 2.60 g of triphenylphosphine, 2.70 g of phthalimide, and 40 mL of THF was added 1.73 g of diethyl azodicarboxylate at room temperature, followed by stirring for 36 hours. To the reaction solution was added ethyl acetate, followed by washing with a 5% aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2.33 g of ({6-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]pyridin-2-yl}oxy)acetic acid as a colorless solid.

Production Example 63

To a mixture of 1266 mg of {2-[(tetrahydro-2H-pyrane-2-yloxy)methyl]pyridin-4-yl}methyl benzoate and 25 ml of methanol was added 1166 mg of pyridinium p-toluenesulfonate, followed by stirring for 2 hours. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added thereto for extraction, and the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 941 mg of [2-(hydroxymethyl)pyridin-4-yl]methyl benzoate as an amorphous substance.

Production Example Compounds 64 to 371 were prepared in the same manner as the methods of Production Examples 1 to 63 and the methods of Examples to be described later, using each of the corresponding starting materials. The structures and the physicochemical data of Production Example Compounds are shown in Tables 14 to 69.

Example 1

To a solution of 808 mg of 3,4-cis-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid, 0.3 ml of phenylethylamine, and 405 mg of HOBt in dichloromethane (20 ml) was added 576 mg of WSC hydrochloride at room temperature, followed by stirring for 2 hours. To the reaction solution was added chloroform, and the organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform) to obtain 902 mg of 3,4-trans-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-N-phenylethyl-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.

Example 2

To a mixture of 202 mg of 3,4-cis-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid and 5 ml of dichloromethane were added 0.055 ml of oxalyl chloride and one drop of DMF under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in 5 ml of THF, and 0.13 ml of phenylethylamine and 0.07 ml of triethylamine were added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, added with ethyl acetate, and washed with water and a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform), and the obtained crude product was then collected by filtration using diethyl ether to obtain 127 mg of 3,4-cis-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-N-phenylethyl-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.

Example 3

To a mixture of 254 mg of 3,4-trans-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-N-[2-(2-pyridinyl)ethyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 5 ml of dichloromethane was added 173 mg of m-chloroperbenzoic acid under ice-cooling, followed by stirring at room temperature overnight. To the reaction solution was added chloroform, washed with a 10% aqueous sodium hydrogen sulfite solution and a saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform-methanol) and then recrystallized from ethanol to obtain 138 mg of 3,4-trans-2-cyclopentyl-3-(2,4-dichlorophenyl)-N-[2-(1-oxidopyridin-2-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.

Example 4

To 654 mg of N-{[(3,4-trans-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}-β-alanine ethyl ester were added 5 ml of THF, 2 ml of methanol, and 5 ml of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring at 50° C. for 3 hours. After neutralization by the addition of 1 M hydrochloric acid, ethyl acetate was added for extraction. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The obtained white solid was recrystallized from ethyl acetate to obtain 294 mg of N-{[(3,4-trans-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}-β-alanine as a colorless powdered crystal.

Example 5

To 410 mg of tert-butyl{2-[3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]ethyl}carbamate was added 4 ml of a 4 M hydrogen chloride/ethyl acetate solution, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and chloroform and a 1 M aqueous sodium hydroxide solution were then added to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to obtain 192 mg of 2-(2-aminoethyl)-3-(2,4-dichlorophenyl)-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless powdered crystal.

Example 6

To a solution of 537 mg of 3,4-trans-2-(trans-4-aminocyclohexyl)-3-(2,4-dichlorophenyl)-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 10 ml of dichloromethane were added 0.33 ml of an aqueous formalin solution and 893 mg of sodium triacetoxyborohydride, followed by stirring at room temperature overnight. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol), and the obtained white solid was recrystallized from ethyl acetate to obtain 82 mg of 3,4-trans-3-(2,4-dichlorophenyl)-2-[trans-4-(dimethylamino)cyclohexyl]-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.

Example 7

To a solution of 2.03 g of 3,4-trans-2-cyclopentyl-1-oxo-4-[(2-phenylethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid in 20 ml of THF was added 810 mg of CDI, followed by stirring under heating at 50° C. for 1 hour. After cooling to room temperature, a mixture of 200 mg of sodium borohydride and 10 ml of water was added thereto, followed by stirring at room temperature for 4 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform), and the obtained solid was recrystallized from ethyl acetate to obtain 255 mg of 3,4-trans-2-cyclopentyl-3-(hydroxymethyl)-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.

Example 8

To 304 mg of (3RS,4RS)—N-(benzyloxy)-3-(4-methyl-3-nitrophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide were added 10 ml of acetic acid and 560 mg of reduced iron, followed by stirring at 50° C. overnight. To the reaction solution was added methanol, followed by filtration through Celite, and after concentrating the mother liquid, ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform:methanol). The obtained solid was made into hydrochloride using a 4 M hydrogen chloride/ethyl acetate solution, and recrystallized from isopropyl alcohol to obtain 180 mg of (3RS,4RS)-3-(3-amino-4-methylphenyl)-N-(benzyloxy)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide hydrochloride as a pale yellow powdered crystal.

Example 9

To 393 mg of 3,4-trans-2-cyclopentyl-3-(hydroxymethyl)-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide were added 10 ml of THF and 44 mg of sodium hydride, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 161 mg of 4-chlorobenzylbromide, followed by stirring at room temperature overnight. To the reaction mixture were added ethyl acetate and water to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) and the obtained solid was crystallized from ether-hexane, and collected by filtration to obtain 134 mg of 3,4-trans-3-{[(4-chlorobenzyl)oxy]methyl}-2-cyclopentyl-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless powdered crystal.

Example 10

To a solution of 573 mg of (3RS,4RS)—N-(2-chloroethyl)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 10 ml of DMF were added 150 mg of sodium iodide and 340 mg of 1H-pyrazole, followed by stirring at 100° C. for 24 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain a colorless crystal. The crystal was recrystallized from ethanol to obtain 176 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-[2-(1H-pyrazol-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless powdered crystal.

Example 11

To a mixture of 270 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 5 ml of pyridine was added 0.11 ml of acetic anhydride, followed by stirring at room temperature for 2 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain a colorless crystal. The obtained crystal was added with diethyl ether and collected by filtration to obtain 55 mg of (3RS,4RS)-2-[(1SR,2SR)-2-acetamidecyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless powdered crystal.

Example 12

To a mixture of 538 mg of (3RS,4RS)-2-{(1SR,2SR)-2-aminocyclohexyl}-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 2.5 ml of pyridine was added 0.15 ml of methanesulfonyl chloride, followed by stirring at room temperature for 6 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a 1 M aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform)) and then recrystallized from ethyl acetate-hexane to obtain 206 mg of (3RS,4RS)—N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless powdered crystal.

Example 13

To a mixed liquid of 200 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 40 ml of dimethoxyethane was added 357 mg of sulfamide, followed by stirring at 80° C. for 2 days. The reaction solution was concentrated, added with chloroform, and then washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol), crystallized from ethyl acetate, and collected by filtration to obtain 62 mg of (3RS,4RS)-2-{(1SR,2SR)-2-[(aminosulfonyl)amino]cyclohexyl}-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.

Example 14

To a mixed liquid of 269 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 5 ml of chloroform was added 0.21 ml of dimethylsulfamoyl chloride, followed by stirring at room temperature for 15 hours, and further at 60° C. for 24 hours. In addition, 500 mg of sodium carbonate was added thereto, followed by stirring at 60° C. for 5 hours. In addition, 0.21 ml of dimethylsulfamoyl chloride was added thereto, followed by stirring at 60° C. for 5 hours. After cooling the reaction solution, a liquid separation operation was then carried out using water and chloroform. The organic layer was washed with 1 M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain a colorless amorphous substance. The obtained amorphous substance was crystallized with ethyl acetate to obtain 99 mg of (3RS,4RS)—N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-{[(dimethylamino)sulfonylamino]amino}cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.

Example 15

To a mixed liquid of 269 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 20 ml of ethanol was added 53 mg of nitrourea, followed by heating under reflux for 1 hour. The reaction solution was cooled and then concentrated, and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol), then crystallized with acetonitrile, and collected by filtration to obtain 155 mg of (3RS,4RS)—N-(benzyloxy)-2-[(1SR,2SR)-2-(carbamoylamino)cyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.

Example 16

To a mixed liquid of 269 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 5 ml of DMF were added 58 mg of sodium carbonate and 119 mg of methyl ethanimidothioate hydrochloride, followed by stirring at 60° C. for 1 hour. Thereafter, while stirring at 60° C., 233 mg of sodium carbonate and 478 mg of methyl ethanimidothioate hydrochloride were further added in four divided portions every 1 hour. After cooling the reaction solution, water was added thereto, followed by extraction with chloroform-isopropyl alcohol (5:1). The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol-aqueous ammonia) and then crystallized with ethyl acetate to obtain 113 mg of (3RS,4RS)—N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(ethanimidoylamino)cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.

Example 17

644 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-N-[2-(2-methoxy-6-methylpyridin-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 1.92 g of pyridine hydrochloride were mixed, followed by warming from room temperature to 200° C. over 15 minutes. The molten mixture was left to be cooled and then subjected to a liquid separation operation using water and ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 480 mg of a low polarity product and 146 mg of a high polarity product. The low polarity product was crystallized with ethyl acetate to obtain 277 mg of (3RS,4RS)-2-[(1SR)-cyclohex-2-en-1-yl]-3-(2,4-dichlorophenyl)-N-[2-(6-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide (Example 17-1) as a white crystal. The high polarity product was recrystallized with ethyl acetate-ethanol to obtain 85 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-N-[2-(6-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide (Example 17-2) as a white crystal.

Example 18

To a mixed liquid of 456 mg of (3RS,4RS)—N-[(3-cyanobenzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 15 ml of DMF was added 139 mg of sodium azide and subsequently 114 mg of ammonium chloride at room temperature, followed by warming to 100° C. and stirring for 12 hours. The reaction solution was cooled to room temperature, then added with water, and extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol). The crude purified product thus obtained was recrystallized with ethanol-water to obtain 171 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-{[3-(2H-tetrazol-5-yl)benzyloxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.

Example 19

A mixture of 730 mg of tert-butyl(3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetate, 5 ml of dichloroethane, and 5 ml of trifluoroacetic acid was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol). The crude purified product thus obtained was recrystallized from ethyl acetate to obtain 184 mg of (3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetic acid as a colorless crystal.

Example 20

To a solution of 330 mg of 3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}benzoic acid in 5 ml of DMF was added 122 mg of CDI, followed by stirring at room temperature for 30 minutes. To the reaction solution were added 71 mg of methane sulfonamide and 0.11 ml of DBU, followed by stirring at room temperature for 3 hours. To the reaction solution was added ethyl acetate, followed by washing with 1 M hydrochloric acid and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain a crude purified product. This was recrystallized with acetonitrile-water to obtain 273 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-N-({3-[(methylsulfonyl)carbamoyl]benzyl}oxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.

Example 21

To a solution of 128 mg of (3RS,4RS)—N-(cyanomethoxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 1.92 ml of methanol was added 0.018 ml of a hydroxylamine solution at room temperature, followed by warming to 40° C. and stirring overnight. The reaction solution was cooled to room temperature and the precipitated crystal was then collected by filtration to obtain 26 mg of (3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.

Example 22

To a mixed liquid of 300 mg of (3RS,4RS)—N-({3-[amino(hydroxyimino)methyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 30 ml of acetonitrile were added 132 mg of 1,1′-carbonothioyl bis(1H-imidazole) and 0.27 ml of DBU under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated and then added with 50 ml of water, and 1 M hydrochloric acid was added thereto until the pH reached 4 to 5. After extracting with ethyl acetate, washing with a saturated aqueous sodium chloride solution and drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol). The crude purified product thus obtained was added with ethyl acetate and collected by filtration to obtain 61 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-{[3-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl]oxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white solid.

Example 23

To a mixed liquid of 280 mg of (3RS,4RS)—N-({3-[amino(hydroxyimino)methyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 10 ml of DMF were added 0.037 ml of pyridine and subsequently 0.084 ml of 2-ethylhexyl chloroformate under ice-cooling, followed by stirring under ice-cooling for 30 minutes. To the reaction solution was added ethyl acetate, followed by washing with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 305 mg of (3RS,4RS)—N-[(3-{amino[({[(2-ethyl hexyl)oxy]carbonyl}oxy)imino]methyl}benzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white amorphous substance. To 290 mg of the present compound was added 6 ml of NMP, followed by stirring at 140° C. for 3 hours. The reaction solution was cooled, and 50 ml of water was then added thereto, followed by stirring. The precipitated solid was collected by filtration. This solid was purified by silica gel column chromatography (eluent: chloroform-methanol), then crystallized with acetonitrile-water, and collected by filtration to obtain 101 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-{[3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl]oxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.

Example 24

To a solution of 500 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-[(1-trityl-1H-1,2,4-triazol-3-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 7.5 ml of methanol was added dropwise 0.25 ml of concentrated hydrochloric acid under ice-cooling, followed by stirring at room temperature for 4 hours. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from ethyl acetate to obtain 282 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(1H-1,2,4-triazol-3-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.

Example 25

A solution of 400 mg of (3RS,4RS)-6-(benzyloxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 245 mg of pentamethylbenzene in 15 ml of trifluoroacetic acid was stirred at room temperature overnight. The trifluoroacetic acid was evaporated under reduced pressure, and ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was solidified with ethyl acetate-isopropyl alcohol and collected by filtration to obtain 350 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-6-hydroxy-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white solid.

Example 26

To a solution of 644 mg of (3RS,4RS)—N-[(4-tert-butoxybenzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 8.4 ml of dichloromethane was added 0.94 ml of trifluoroacetic acid under ice-cooling, followed by stirring at room temperature for 1 hour. The solution was concentrated under reduced pressure and then recrystallized from ethyl acetate to obtain 363 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-hydroxy-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.

Example 27

To a mixed liquid of 350 mg of ethyl 1,2-cis-2-[3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]cyclohexanecarboxylate, 25 ml of THF, and 25 ml of ethanol was added 1 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 60 hours, and further at 60° C. for 8 hours. After evaporating the solvent, a liquid separation operation was carried out using 1 M hydrochloric acid and chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol). The obtained residue was washed with diisopropyl ether-ethyl acetate to obtain 144 mg of ethyl 1,2-trans-243,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]cyclohexanecarboxylate as a white solid.

Example 28

To a mixed liquid of 334 mg of 2-(trimethylsilylethyl) 1,2-cis-243,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(pyridin-2-ylmethoxy)carbomoyl]-3,4-dihydroisoquinolin-2(1H)-yl]cyclohexanecarboxylate and 5 ml of THF was added 0.60 ml of a 1 M solution of tetrabutylammonium fluoride in THF, followed by stirring at room temperature for 4 hours. To the reaction solution was added 20 ml of DMF, followed by stirring at room temperature for 2 hours, then evaporating the THF under reduced pressure, and stirring again at room temperature for 20 hours. The reaction solution was warmed to 60° C. and stirred for 2 hours, and then 0.30 ml of a 1 M solution of tetrabutylammonium fluoride in THF was further added thereto, followed by stirring at 60° C. for 2 hours. After evaporating the solvent under reduced pressure, 1 M hydrochloric acid was added, and a 1 M aqueous sodium hydroxide solution was added thereto until the pH reached 2. The solution was extracted with ethyl acetate and chloroform, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol), and the obtained residue was then washed with ethyl acetate to obtain 156 mg of 1,2-cis-2-[3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(pyridin-2-ylmethoxy)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]cyclohexanecarboxylic acid as a white solid.

Example 29

To a solution of 1000 mg of (3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 26 ml of dichloroethane was added dropwise 0.4 ml of pyridine, and then 0.23 ml of methyl chloro(oxo)acetate was added dropwise thereto under ice-cooling, followed by stirring at 0° C. for 10 minutes, at room temperature for 20 minutes, and at 80° C. for 2 hours. The reaction solution was cooled to room temperature, washed with 0.1 M hydrochloric acid and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 670 mg of methyl 3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazole-5-carboxylate as a white amorphous substance.

Example 30

To 400 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid were added 8 ml of DMF, 243 mg of O-[3-(tetrahydro-2H-pyran-2-yl oxy)benzyl]hydrokylamine, 159 mg of HOBt, and 243 mg of WSC, followed by stirring at room temperature for 3 hours. The reaction solution was added with ethyl acetate and water to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. To the residue was added methanol, and concentrated hydrochloric acid was added dropwise thereto under ice-cooling, followed by stirring under ice-cooling for 1 hour. The precipitated crystal was collected by filtration to obtain 275 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-[(3-hydroxybenzyl)oxy]-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.

Example 31

To a solution of 323 mg of (3-{[({[(3RS,4RS-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazol-5-yl)methyl acetate in 6.5 ml of methanol was added 66 mg of potassium carbonate, followed by stirring at room temperature for 3 hours. To the reaction solution was added ethyl acetate, followed by washing with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and then recrystallized from ethyl acetate to obtain 157 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]methoxy}-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.

Example 32

By condensing 4-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)butanoic acid and ethylamine using WSC and HOBt in accordance with Example 1, (3RS,4RS)-3-(2,4-dichlorophenyl)-N-[4-(ethylamino)-4-oxobutyl]-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide was obtained as a colorless crystal.

Example 33

By condensing 3,4-trans-2-cyclopentyl-1-oxo-4-[(2-phenylethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and benzylamine using WSC and HOBt in accordance with Example 1, 3,4-trans-3-benzylcarbamoyl-2-cyclopentyl-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide was obtained as a colorless crystal.

Example 34

By condensing cis-4-[3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]cyclohexanecarboxylic acid and 1-methylpiperazine using WSC and HOBt in accordance with Example 1, 3,4-trans-3-(2,4-dichlorophenyl)-2-{cis-4-[(4-methylpiperazin-1-yl)carbonyl]cyclohexyl}-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide was obtained as a colorless crystal.

Example 35

By condensing (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and hydroxyacetic acid using WSC and HOBt in accordance with Example 1, (3RS,4RS)—N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(glycoloylamino)cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide was obtained as a colorless crystal.

Example 36

By treating 3,4-trans-2-cyclopentyl-3-(3-pyridinyl)-1-oxo-N-phenylethyl-1,2,3,4-tetrahydroisoquinoline-4-carboxamide with m-chloroperbenzoic acid in accordance with Example 3, 3,4-trans-2-cyclopentyl-3-(1-oxidopyridin-3-yl)-1-oxo-N-phenylethyl-1,2,3,4-tetrahydroisoquinoline-4-carboxamide was obtained as a colorless crystal.

Example 37

By treating 3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-N-phenylethyl-2-[2-(3-pyridinyl)ethyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide with m-chloroperbenzoic acid in accordance with Example 3, 3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-N-phenylethyl-2-[2-(1-oxidopyridin-3-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide was obtained as a colorless crystal.

Example 38

By treating methyl 4-{3,4-trans-2-cyclopentyl-1-oxo-4-[(2-phenylethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinolin-3-yl}benzoate with a 1 M aqueous sodium hydroxide solution in accordance with Example 4, 4-{3,4-trans-2-cyclopentyl-1-oxo-4-[(2-phenylethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinolin-3-yl}benzoic acid was obtained as a colorless crystal.

Example 39

By treating ethyl 4-{3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}propanoate with a 1 M aqueous sodium hydroxide solution in accordance with Example 4, 4-{3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}propanoic acid was obtained as a colorless crystal.

Example 40

By treating 4-{[({[(3RS,4RS)-trans-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-trans-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}benzoic acid with CDI and then with sodium borohydride in accordance with Example 7, (3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-1,2-trans-2-hydroxycyclohexyl]-N-{[4-(hydroxymethyl)benzyl]oxy}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide was obtained as a colorless crystal.

Example 41

To a mixed liquid of 400 mg of (3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 40 ml of acetonitrile were added 108 mg of CDI and 0.4 ml of DBU under ice-cooling, followed by stirring at room temperature overnight. After concentrating the reaction solution, a saturated aqueous ammonium chloride solution and ethyl acetate were added thereto, followed by extraction. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from ethyl acetate to obtain 40 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-N-[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.

Example 42

To a mixture of 300 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid and 6 ml of DMF were added {5-[(aminooxy)methyl]pyrazin-2-yl}methyl acetate dihydrochloride, 0.16 ml of triethylamine, 119 mg of HOBt, and 200 mg of WSC, followed by stirring at room temperature for 3 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. To the residue were added 4.5 ml of methanol and 2.4 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at 0° C. for 2 hours, and then 1 M hydrochloric acid was added thereto for neutralization. Chloroform was added thereto for extraction, and the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: chloroform-methanol) and then recrystallized from ethyl acetate to obtain 73 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)pyrazin-2-yl]methoxy}-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.

Example 43

To a solution of 350 mg of (3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 9.2 ml of dichloroethane was added dropwise 0.15 ml of pyridine. To the reaction solution was added dropwise 0.095 ml of 2-chloro-2-oxoethyl acetate under ice-cooling, followed by 10 minutes at 0° C., 20 minutes at room temperature and then heating under reflux for 8 hours. The solution was cooled to room temperature, and ethyl acetate was added thereto, followed by washing with 0.1 M hydrochloric acid and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 323 mg of (3-{[({[(3RS,4RS-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazol-5-yl)methyl acetate.

Example 44

To a solution of 600 mg of methyl 5-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}thiophene-3-carboxylate in 40 mL of THF was added 45 mg of lithium aluminum hydride at −78° C. The solution was warmed to 0° C., followed by stirring for 3 hours. Sodium sulfate decahydrate was added thereto, followed by stirring for 1 hour. After removing sodium sulfate by filtration, the organic layer was dried by adding anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 162 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[4-(hydroxymethyl)-2-thienyl]methoxy}-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white solid.

Example 45

To a solution of 500 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-6-nitro-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 10 ml of methanol-dioxane (1:1) was added 500 mg of Raney nickel, followed by stirring for 30 minutes under a hydrogen atmosphere. The catalyst was removed by filtration and the solvent was concentrated under reduced pressure to obtain 300 mg of (3RS,4RS)-6-amino-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a black solid.

Example 46

To a solution of 300 mg of (3RS,4RS)-6-amino-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, 213 mg of formaldehyde, and 11 mg of sulfuric acid in 5 ml of THF was added 125 mg of sodium borohydride at 0° C., followed by stirring for 2 hours. The reaction solution was poured into ice water and the organic layer was extracted with ethyl acetate. The solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by reverse-phase silica gel column chromatography (eluent: acetonitrile-water) to obtain 10 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-6-(dimethylamino)-2-(1R,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a yellow solid.

Example 47

A solution of 343 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-(2-hydrazino-2-oxoethoxy)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 6.9 ml of THF was cooled to 0° C., and 116 mg of 1,1′-carbonyldiimidazole and 0.12 ml of triethylamine were added thereto, followed by stirring at 0° C. for 2 hours, and then stirring at room temperature overnight. 0.1 M hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The solution was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 221 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-[(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white powder crystal.

Example 48

To a mixed liquid of 420 mg of benzyl ({6-[2-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}oxy)acetate, 5 ml of DMF, and 5 ml of ethanol was added 84 mg of 5% palladium/carbon, followed by stirring at room temperature for 15 minutes under a hydrogen atmosphere. After separating the palladium/carbon by filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 78 mg of ({6-[2-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}oxy)acetic acid as a white solid.

Example 49

A solution of 480 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[6-(hydroxymethyl)pyridin-2-yl]methoxy}-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 4.8 ml of dichloromethane was cooled to 0° C., 4.5 mg of DMAP and 0.13 ml of pyridine were added, and then 0.7 ml of acetic anhydride was added dropwise, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain (6-{[(acetyl{[3-(2,4-dichlorophenyl)-2-{2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}pyridin-2-yl)methyl acetate.

Example 50

A solution of 714 mg of (3R,4R)-3-(2,4-dichlorophenyl)-N-{1-[6-(hydroxymethyl)pyridin-2-yl]ethyl}-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 14.3 ml of chloroform was cooled to 0° C., and 0.23 ml of triethylamine, 0.16 ml of acetic anhydride, and 6.8 mg of DMAP were added thereto in this order, followed by stirring at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate-water was added thereto for liquid separation, followed by washing with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain {6-[1-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}methyl acetate.

Example 51

To 591 mg of [({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]acetic acid were added 8 ml of DMF, 200 mg of tert-butyl hydrazinecarboxylate, 205 mg of HOBt, and 388 mg of WSC hydrochloride, followed by stirring at room temperature for 3 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. 7.7 ml of dichloromethane was added thereto, followed by cooling to 0° C., and 1.2 ml of trifluoroacetic acid was added thereto, followed by stirring at room temperature for 5 hours. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from ethyl acetate to obtain 417 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-(2-hydrazino-2-oxoethoxy)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white powder crystal.

Example 52

A solution of 153 mg of (6-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1-oxidopyridin-3-yl)methyl benzoate in 3 ml of ethanol was cooled to 0° C., and 32 mg of sodium hydroxide was added thereto, followed by stirring at 0° C. for 2 hours. The solution was neutralized with 1 M hydrochloric acid, and a saturated aqueous sodium hydrogen carbonate solution and chloroform were added for liquid separation. The organic layer was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 24 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)-1-oxidopyridin-2-yl]methoxy}-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide.

Example 53

To a solution of 700 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid, 351 mg of 1-phenylmethanesulfonamide, and 334 mg of DMAP in 10.5 ml of DMF was added 525 mg of WSC/hydrochloride, followed by stirring at room temperature overnight. 0.1 M hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol), and ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were then added thereto for liquid separation. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added thereto, and the precipitated solid was collected by filtration to obtain 33 mg of (3RS,4RS)—N-(benzylsulfonyl)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless solid.

Example 54

To a solution of 566 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-[(2,2-dimethyl-4H-[1,3]dioxino[5,4-b]pyridin-6-yl)methoxy]-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 11.3 ml of THF was added 3.2 ml of 1 M hydrochloric acid, followed by stirring at room temperature for 2 hours. 1.6 ml of 1 M hydrochloric acid was further added, followed by stirring for 2 days. The solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from ethyl acetate to obtain 196 mg of rel-(3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-hydroxy-6-(hydroxymethyl)pyridin-2-yl]methoxy}-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.

Example 55

To a solution of 433 mg of 6-{[(acetyl{[3-(2,4-dichlorophenyl)-2-{2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1-oxidopyridin-2-yl)methyl acetate in 8.7 ml of methanol was added 160 mg of potassium carbonate, followed by stirring. The solution was added with 1 M hydrochloric acid and then with a saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol). Ethyl acetate, ethanol, and diisopropyl ether were added thereto for solidification to obtain 164 mg of 3-(2,4-dichlorophenyl)-N-{[6-(hydroxymethyl)-1-oxidopyridin-2-yl]methoxy}-2-{2-[(methylsulfonyl)amino]cyclohexyl }-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless solid.

Example 56

To a solution of 777 mg of {6-[1-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]-1-oxidopyridin-2-yl}methyl acetate in 17 ml of methanol was added 0.21 ml of hydrazine monohydrate, followed by stirring for one week. Ethyl acetate was added thereto, followed by stirring for a while and concentrating, and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol). Ethyl acetate and diisopropyl ether were used to make a powder, thereby obtaining 501 mg of (3R,4R)-3-(2,4-dichlorophenyl)-N-{1-[6-(hydroxymethyl)-1-oxidopyridin-2-yl]ethyl}-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless solid.

Example 57

A mixture of 590 mg of 3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}benzoic acid, 217 mg of CDI, and 9 ml of DMF was stirred at 50° C. for 1 hour, and 241 mg of guanidine carbonate was then added thereto, followed by stirring at the same temperature for 3 hours. The reaction solution was left to be cooled and the solvent was then evaporated under reduced pressure. The residue was diluted with ethyl acetate, and washed with a 5% saturated aqueous sodium hydrogen carbonate solution and then with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from acetonitrile to obtain 348 mg of (3RS,4RS)—N-({3-[(diaminomethylene)carbamoyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless solid.

Example 58

To a mixture of 990 mg of 4-methoxybenzyl(3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl)amino]ethyl}phenyl)acetate and 10 ml of ethylene chloride was added 10 ml of trifluoroacetic acid at room temperature, followed by stirring for 4 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 20 mL of methanol, and 20 mL of a 5% saturated aqueous sodium hydrogen carbonate solution was added thereto at room temperature, followed by stirring for 30 minutes. The organic solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and neutralized with 1 M hydrochloric acid. The product was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 339 mg of (3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenyl)acetic acid as a colorless solid.

Example 59

To a mixture of 980 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-N-[2-(3-hydroxyphenyl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, 1160 mg of triphenylphosphine, 1080 mg of tert-butyl(2R)-2-hydroxypropanate, and 30 mL of THF was added 770 mg of diethyl azodicarboxylate at room temperature, followed by stirring for 12 hours. The reaction solution was diluted with ethyl acetate and washed with a 5% saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 1460 mg of tert-butyl (2S)-2-(3-{24({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenoxy)propanate as a yellow solid.

The compounds of Examples 60 to 899 as shown in Tables below were prepared in the same manner as the methods of Examples 1 to 59, using each of the corresponding starting materials. The structures of each Example Compound are shown in Tables 70 to 275, and the production processes and the physicochemical data of each Example Compound are shown in Tables 276 to 300.

Furthermore, the structures of the other compounds of the present invention are shown in Tables 301 to 302. These can be easily synthesized by using the production processes as described above, the methods described in Examples, methods obvious to a skilled person in the art, or modified methods thereof.

TABLE 14 PEx Syn Structure Data Note 64 P34

ESI+: 471 65 P34

ESI+: 456 34-2 P34

ESI−: 434 racemic mixture 34-1 P34

ESI−: 434 racemic mixture 66 P34

ESI+: 430

TABLE 15 67 P34

ESI+: 462 68 P34

ESI+: 430 69 P34

ESI+: 456 70 P34

ESI+: 462 33-1 P33

ESI+: 404 racemic mixture

TABLE 16 33-2 P33

ESI+: 404 racemic mixture 71 P34

ESI+: 471 72 P33

FAB+: 532 racemic mixture 30 P30

ESI+: 214 18 P18

FAB+: 372 73 P31

ESI+: 244 74 P31

ESI+: 244

TABLE 17 75 P31

ESI+: 276 31 P31

FAB+: 340 37 P37

ESI+: 553 racemic mixture  5 P5

FAB+: 244 76 P17 P14

FAB+: 313 77 P14

FAB+: 318 78 P42

FAB+: 340

TABLE 18 79 P42

FAB+: 340 80 P14

ESI+: 330 14 P14

FAB+: 332 81 P14

FAB+: 280 82 P14

FAB+: 257 83 P14

FAB+: 279 84 P14

FAB+: 246 85 P14

FAB+: 332

TABLE 19 86 P14

FAB+: 487 87 P14

FAB+: 285 88 P14

FAB+: 376 89 P42

FAB+: 368 90 P14

FAB+: 326 91 P14

FAB+: 273 92 P14

ESI+: 342

TABLE 20 93 P14

ESI+: 342 94 P42

FAB+: 454 95 P14

FAB+: 368 96 P42

FAB+: 384 97 P42

FAB+: 354 98 P14

EI+: 238 99 P42

FAB+: 326

TABLE 21 100 P14

EI+: 247  42 P42

FAB+: 273 101 P14

FAB+: 260 102 P14

ESI+: 330 103 P14

ESI+: 280 104 P14

FAB+: 298 105 P14

FAB+: 260 106 P14

FAB+: 260

TABLE 22 107 P14

FAB+: 269 108 P14

ESI+: 318 109 P14

ESI+: 330  25 P25

FAB+: 344 racemic mixture  15 P15

FAB+: 263  43 P43

FAB+: 263 110 11

ESI+: 309

TABLE 23 111 11

FAB+: 503 racemic mixture 112 P34

FAB+: 539 racemic mixture 113 P34

ESI+: 433 114 P34

FAB+: 463 racemic mixture 115 P34

FAB+: 451 racemic mixture 116 P34

FAB+: 447 racemic mixture

TABLE 24 117 P34

ESI+: 463 racemic mixture 118 P34

ESI+: 463 racemic mixture 119 P34

FAB+: 451 racemic mixture 120 P34

ESI+: 465 racemic mixture 121 P33

FAB+: 491 122 P33

FAB+: 488 1′,2′-trans

TABLE 25 123 P33

FAB+: 562 1′,2′-trans 124 P33

FAB+: 462 1′,2′-trans 125 P33

FAB+: 405 126 P35

ESI+: 491 racemic mixture 127 P34 P35

ESI+: 445 1′-2′-trans, 3,4-trans, diastereo mixture  35 P35

ESI+: 461 racemic mixture

TABLE 26 128 P35

ESI+: 461  11 P11

CI+: 210  17 P17

EI+: 190  20 P20

CI+: 365  19 P19

EI+: 292  4 P4

CI+: 228  21 P21

CI+: 221 129 P36

FAB+: 569 racemic mixture

TABLE 27 130 P36

FAB+: 557 racemic mixture 131 P36

FAB+: 557 racemic mixture 132 P34 P35 P36

FAB+: 569 racemic mixture 133 P34 P35 P36

FAB+: 569 racemic mixture

TABLE 28 134 P34 P35 P36

FAB+: 539 racemic mixture 135 P34 P35 P36

FAB+: 539 racemic mixture 136 P36

ESI+: 553 racemic mixture 137 P36

FAB+: 569 racemic mixture 138 P36

ESI+: 569 racemic mixture

TABLE 29 139 P34 P35 P36

ESI+: 535 1′,2′-trans, 3,4-trans, racemic mixture 140 P34 P35 P36

FAB+: 529 1′,2′-trans, 3,4-trans, racemic mixture 141 P34 P35 P36

FAB+: 513 1′,2′-trans, 3,4-trans, racemic mixture 142 P36

ESI+: 523 1′,2′-trans, 3,4-trans, racemic mixture

TABLE 30 143 P36

ESI+: 523 1′,2′-trans, 3,4-trans, racemic mixture 144 P35 P36

ESI+: 530 1′,2′-trans, 3,4-trans, racemic mixture 145 P34 P35 P36

FAB+: 507 1′,2′-trans, 3,4-trans, racemic mixture 146 P36

EI+: 316 147 P36

ESI+: 519 1′,2′-trans, 3,4-trans, racemic mixture, less polar

TABLE 31 148 P36

ESI+: 519 1′,2′-trans, 3,4-trans, racemic mixture, more polar 149 P36

ESI+: 499 1′,2′-trans, 3,4-trans, racemic mixture, less polar 150 P36

ESI+: 499 1′,2′-trans, 3,4-trans, racemic mixture, more polar  36 P36

ESI+: 539 racemic mixture

TABLE 32 151 P36

ESI+: 539 152 P22

FAB+: 331  22 P22

FAB+: 279 153 P22

FAB−: 209 154 P22

FAB+: 293 155 P34

FAB+: 426 1′,2′-trans, 3,4-trans, racemic mixture, less polar

TABLE 33 156 P34

FAB+: 426 1′,2′-trans, 3,4-trans, racemic mixture, more polar 157 P34

FAB+: 434 1′,2′-trans, 3,4-trans, racemic mixture, less polar 158 P34

FAB+: 434 1′,2′-trans, 3,4-trans, racemic mixture, more polar 159 P34

FAB+: 486 160 P34

ESI+: 424 1′,2′-trans, 3,4-trans, 161 P34

ESI+: 511 3,4-trans, diastereo mixture

TABLE 34 162 P34

FAB+: 497 racemic mixture 163 P34

ESI−: 485 3,4-trans, diastereo mixture 164 P34

ESI−: 485 3,4-trans, diastereo mixture 165 P34

FAB+: 533 3,4-trans, diastereo mixture 166 P34

ESI+: 422 1′,2′-trans, 3,4-trans, racemic mixture, more polar

TABLE 35 167 P34

ESI+: 422 1′,2′-trans, 3,4-trans, racemic mixture, less polar 168 P34

FAB+: 486 169 P34

FAB+: 394 1′,2′-trans, 3,4-trans, racemic mixture, less polar 170 P34

FAB+: 394 1′,2′-trans, 3,4-trans, racemic mixture, more polar 171 P34

FAB+: 531 racemic mixture

TABLE 36 172 P34 P35 P36 P38

ESI+: 461 1′,2′- trans, 3,4- trans, racemic mixture  38 P38

ESI+: 512 racemic mixture 173 P38

ESI+: 502 1′,2′- trans, 3,4- trans, racemic mixture 174 P38

ESI+: 511

TABLE 37 175 P38

FAB+: 541 racemic mixture 176 P38

FAB+: 541 racemic mixture 177 P38

ESI+: 475 racemic mixture 178 P38

FAB+: 541 racemic mixture

TABLE 38 179 P38

ESI+: 541 racemic mixture 180 P38

ESI+: 485 1′,2′-trans, 3,4-trans, racemic mixture 181 P38

ESI+: 501 1′,2′-trans, 3,4-trans, racemic mixture 182 P38

ESI+: 479 1′,2′-trans, 3,4-trans, racemic mixture 183 P38

FAB+: 541 racemic mixture

TABLE 39 184 P34 P35 P36 P38

ESI−: 617 racemic mixture 185 P38

FAB+: 529 racemic mixture 186 P38

FAB+: 529 racemic mixture 187 P38

FAB+: 511 188 P38

FAB+: 511

TABLE 40 189 P38

FAB+: 525 racemic mixture  1 P1

ESI−: 285  7 P7

CI+: 183 190 P39

ESI+: 177 191 P39

EI+: 180  39 P39

FAB+: 269 192 P23

FAB+: 215  23 P23

EI+: 251

TABLE 41  27 P27

FAB+: 303  16 P16

EI+: 172 193 P16

EI+: 222 194 P16

FAB+: 267 195 P16

FAB+: 209 196 P16

FAB−: 307 197 P16

ESI+: 261 [M + Na] 198 P16

ESI+: 239

TABLE 42  24 P24

EI+: 237 199 P24

EI+: 237  2 P2

ESI+: 225  12 P12

EI+: 181 200 P8

FAB+: 342  8 P8

FAB+: 298 201 P8

FAB+: 271 202 P8

APCI+: 384

TABLE 43 203 P8

ESI+: 384 204 P8

ESI+: 412 205 P8

FAB+: 356 206 P8

ESI−: 368 207 P56 P8

FAB+: 383 208 P8

ESI+: 370 209 P40

CI+: 139

TABLE 44 210 P40

FAB+: 210 211 P8 P40

CI+: 140 212 P8 P40

FAB+: 198  40 P40

FAB+: 141 213 P8 P40

FAB+: 259 214 P40

FAB+: 196 215 P40

FAB+: 155 216 P40

FAB+: 164 217 P40

FAB+: 210 218 P8 P40

FAB+: 126

TABLE 45  26 P26

FAB+: 244 racemic mixture 219 P25 P26

FAB+: 244 racemic mixture 220 P26

ESI+: 179 221 P26

FAB+: 172 222 P26

FAB+: 193  41 P41

FAB+: 128  28 P28

FAB+: 169  3 P3

CI+: 265 223 P40

FAB+: 202

TABLE 46 224 P40

FAB+: 183 225 P40

EI+: 148 226 P14 P9

FAB+: 155 227 P9

CI+: 212  9 P9

CI+: 168 228 P40

ESI+: 168 229 P40

FAB+: 150 230 P9

EI+: 126 231 28 P9

CI+: 130 232 P8 P9

CI+: 145 233 P8 P9

EI+: 138

TABLE 47 234 P9

EI+: 253 235 P9

CI+: 238 236 P9

EI+: 223 237 P9

FAB+: 324 238 P9

CI+: 196 239 P9

CI+: 212 240 P9

FAB+: 357 241 P9

CI+: 143

TABLE 48 242 P9

FAB+: 202 243 P9

CI+: 130 244 P9

CI+: 143 245 P9

FAB+: 238 246 P14 P40

FAB+: 196 247 P9

CI+: 231 248 P8 P9

CI+: 180 249 P9

CI+: 212 250 P9

CI+: 130 251 P9

CI+: 130 252 P9

EI+: 115

TABLE 49 253 P40

FAB+: 188 254 P9

ESI+: 254 255 P9

ESI+: 254 256 P9

ESI+: 282 257 P9

CI+: 226 258 P9

ESI+: 254 259 P9

ESI+: 240 260 P9

ESI+: 200

TABLE 50 261 P9

ESI+: 200 262 P9

ESI+: 200 263 P9

ESI+: 150 264 P9

ESI+: 240 265 P32

EI+: 152 266 P32

ESI+: 114 267 P32

ESI+: 146  32 P32

ESI+: 211  13 P13

FAB+: 141  29 P29

FAB+: 139

TABLE 51  10 P10

FAB+: 196  6 P6

ESI−: 242 268 P33

ESI+: 478 racemic mixture 269 P35 P36

ESI+: 584 racemic mixture 270 P42

FAB+: 454 271 P38

ESI+: 556 racemic mixture

TABLE 52 272 P33

ESI+: 464 273 P42

FAB+: 261 274 P9

FAB+: 324 275 P35 P36

ESI+: 569  55 P55

ESI+: 342

TABLE 53 276 P8

ESI+: 342 277 P9 P40

FAB+: 131 278 P9

ESI+: 254 279 P32

ESI+: 212 280 P51 P40

ESI+: 123 281 P14

ESI+: 303 232 P8

ESI+: 333

TABLE 54  57 P57

FAB+: 240 283 P9

ESI+: 173 284 P38

EI+: 186  52 P52

EI+: 165 285 P60

CI+: 243 286 P9

FAB+: 203  62 P62

ESI+: 369 287 P32

ESI+: 212

TABLE 55 288 20

ESI−: 327 289 P8 P9

FAB+: 203 290 P8 P9

FAB+: 181 291 P19

CI+: 321 292 P8

ESI+: 310 293 P26

FAB+: 229 294 P14

ESI+: 402 295 P9

CI+: 274 296 P9

FAB+: 180

TABLE 56 297 20

FAB−: 341 298 P26

FAB+: 243 299 P16

ESI+: 170 300 P8 P9

NMR1: 2.50 (2H, s), 4.50 (3H, s), 6.00 (2H, s), 6.13-6.16 (1H, m), 6.71-6.73 (1H, m), 11.84 (1H, s) 301 P62

ESI+: 269 302 12

ESI+: 603 racemic mixture

TABLE 57  44 P44

ESI+: 565 racemic mixture  58 P58

EI+: 252 303 P32

ESI+: 239 304 P62

FAB+: 381 305 P8

FAB+: 341 306 P9

CI+: 211

TABLE 58 307 P32

ESI+: 252 308 P4

FAB+: 245 309 P8

FAB+: 390 310 P9

FAB+: 260 53-1 P53

CI+: 182 53-2 P53

EI+: 180 311 P14

ESI+: 316

TABLE 59 312 P48

CI+: 268 313 P23

FAB+: 272  50 P50

FAB+: 266 314 P12

FAB+: 244 315 P4

FAB+: 328  63 P63

FAB+: 244 316 P14

ESI+: 332

TABLE 60 317 P8 P9 P40

ESI+: 259 318 P14

FAB+: 420 319 P9

CI+: 290 320 P48

FAB+: 268 321 P14 P9

CI+: 274 322 P23

EI+: 271  61 P61

FAB+: 167 323 P19

CI+: 275, 277

TABLE 61 324 P16 P8 P9

ESI+: 216  46 P46

ESI+: 171  51 P51

CI+: 153 325 P48

ESI−: 222 326 P55

ESI−: 222 327 P32

APCI+: 213 328 P8

ESI+: 316  47 P47

APCI+: 169 329 P9

ESI+: 186

TABLE 62 330 P19

APCI+: 279 331 P30

FAB+: 239 332 P55

FAB+: 343 333 P23

ESI+: 228 334 P57

ESI+: 387 335 P16

FAB+: 171 336 P32

ESI+: 214 337 P61 P51

EI+: 152

TABLE 63 338 P61

EI+: 249 339 P26

ESI+: 287 340 P48

ESI+: 214 341 P8

APCI−: 314 342 P51

FAB+: 236 343 P16

FAB−: 199 344 P56

FAB+: 386

TABLE 64 345 P26

ESI+: 286 346 P61 P51

CI+: 222  54 P54

FAB+: 139 347 P8

NMR1: 1.19 (3H, t, J = 9.0 Hz), 3.90 (2H, s), 4.10 (2H, q, J = 9.0 Hz), 5.27 (2H, s), 6.87 (1H, d, J = 4.2 Hz), 7.10 (1H, d, J = 4.2 Hz), 7.82-7.93 (4H, m)  48 P48

CI+: 218 348 P23

EI+: 221

TABLE 65 349 P61 P51

FAB+: 252 350 P36

ESI+: 506 racemic mixture 351 P38

ESI+: 478 racemic mixture  49 P49

CI+: 184 352 P61 P51

FAB+: 195

TABLE 66  56 P56

ESI+: 248  59 P59

ESI+: 300 353 P56

EI+: 264 354 P61 P51

CI+: 266 355 P23

ESI+: 296  45 P45

NMR1: 5.31 (1H, d, J = 8.2 Hz), 5.79 (1H, d, J = 13.3 Hz), 6.75 (1H, dd, J = 13.3, 8.2 Hz), 8.07 (1H, s), 8.25 (1H, s), 9.92 (1H, s)

TABLE 67 356 P8

NMR1: 3.92 (3H, s), 5.22 (2H, s), 6.35 (1H, d, J = 3.0 Hz), 6.85 (1H, d, J = 3.0 Hz), 7.82-7.88 (4H, m) 357 P16 P8

NMR1: 5.17 (1H, d, J = 8.1 Hz), 5.62 (2H, d, J = 13.2 Hz), 6.66 (1H, dd, J = 13.2, 8.1 Hz), 7.50 (1H, s), 7.58 (1H, s), 7.83-7.89 (4H, m) 358 P33 P34

ESI+: 450 racemic mixture 359 P9

ESI+: 152 360 P48

ESI+: 224

TABLE 68 361 P8 P9

NMR1: 3.38-3.52 (2H, m), 4.48-4.55 (1H, m), 4.65 (2H, s), 4.66-4.71 (1H, s), 5.15 (1H, d, J = 3.9 Hz), 6.08 (2H, s), 6.98 (1H, s), 7.22 (1H, s) 362 P23

ESI+: 228 363 P33 P34

ESI−: 480 diastereomer of PEx364, racemic mixture, 1′,2′-trans, 3,4-trans 364 P33 P34

ESI+: 482 diastereomer of PEx363, racemic mixture, 1′,2′-trans, 3,4-trans 365 P33 P34

ESI−: 480 diastereomer of PEx366, racemic mixture, 1′,2′-trans, 3,4-trans

TABLE 69 366 P33 P34

ESI+: 482 diastereomer of PEx365, racemic mixture, 1′,2′-trans, 3,4-trans 367 P33 P34

ESI+: 486 368 P33 P34

ESI+: 511 racemic mixture  60 P60

EI+: 182 369 P19

EI+: 260, 262 370 P48

ESI−: 206 371 P23

ESI+: 212

TABLE 70 Ex Structure Note 60

61

62

63

racemic mixture 64

TABLE 71 65

66

racemic mixture 67

racemic mixture 68

69

racemic mixture

TABLE 72 70

racemic mixture 71

72

racemic mixture 73

racemic mixture 74

racemic mixture

TABLE 73 75

racemic mixture  1

racemic mixture 76

racemic mixture 77

racemic mixture 78

TABLE 74  3

racemic mixture 79

racemic mixture 80

racemic mixture 81

82

racemic mixture

TABLE 75 83

racemic mixture 84

racemic mixture 85

racemic mixture 86

racemic mixture 37

racemic mixture

TABLE 76 87

88

racemic mixture 89

racemic mixture 90

91

racemic mixture

TABLE 77 92

racemic mixture 93

racemic mixture 94

95

racemic mixture 96

racemic mixture 97

racemic mixture

TABLE 78  98

racemic mixture  99

racemic mixture 100

racemic mixture 101

racemic mixture 102

103

racemic mixture

TABLE 79 104

racemic mixture 105

racemic mixture 106

racemic mixture 107

racemic mixture 108

 2

racemic mixture

TABLE 80 109

racemic mixture  39

racemic mixture 110

racemic mixture 111

racemic mixture  4

racemic mixture

TABLE 81 112

113

racemic mixture 114

racemic mixture 115

racemic mixture 116

racemic mixture 117

racemic mixture

TABLE 82 118

119

racemic mixture 120

racemic mixture 121

racemic mixture 122

racemic mixture 123

racemic mixture

TABLE 83 124

racemic mixture  36

racemic mixture 125

racemic mixture 126

racemic mixture 127

racemic mixture  38

racemic mixture

TABLE 84 128

racemic mixture  7

racemic mixture 129

racemic mixture 130

racemic mixture  10

racemic mixture

TABLE 85 131

racemic mixture 132

racemic mixture 133

racemic mixture 134

racemic mixture

TABLE 86 135

racemic mixture 136

racemic mixture 137

racemic mixture 138

racemic mixture

TABLE 87 139

racemic mixture 140

racemic mixture 141

racemic mixture 142

racemic mixture

TABLE 88 143

racemic mixture 144

racemic mixture 145

3,4-trans, diastereo mixture 146

racemic mixture

TABLE 89 147

 9

racemic mixture 148

1′,2′-trans, 3,4-trans, diastereomer of Ex149, more polar 149

1′,2′-trans, 3,4-trans, diastereomer of Ex148, more polar

TABLE 90  11

racemic mixture 150

racemic mixture 151

152

racemic mixture 153

racemic mixture

TABLE 91 154

155

156

157

158

1′,2′-trans, 3,4-trans, diastereo mixture

TABLE 92 159

1′,2′-trans, 3,4-trans, diastereomer of Ex160, less polar 160

1′,2′-trans, 3,4-trans, diastereomer of Ex159, more polar 161

racemic mixture 162

racemic mixture 163

racemic mixture

TABLE 93 164

racemic mixture 165

racemic mixture 166

racemic mixture 167

racemic mixture 168

1′,2′-cis, 3,4-trans, racemic mixture

TABLE 94 169

racemic mixture 170

racemic mixture 171

racemic mixture 172

racemic mixture 173

racemic mixture

TABLE 95 174

racemic mixture 175

racemic mixture 176

racemic mixture 177

racemic mixture 178

racemic mixture

TABLE 96  34

racemic mixture 179

racemic mixture 180

racemic mixture 181

racemic mixture 182

racemic mixture

TABLE 97 183

racemic mixture 184

185

1′,2′-trans, 3,4-trans, diastereomer of Ex186, less polar 186

1′,2′-trans, 3,4-trans, diastereomer of Ex185 187

racemic mixture

TABLE 98 188

189

1′,2′-trans, 3,4-trans, diastereomer of Ex190, less polar 190

1′,2′-trans, 3,4-trans, diastereomer of Ex189, more polar 191

3,4-trans, distereomer of Ex192, less polar 192

3,4-trans, distereomer of Ex191, more polar

TABLE 99 193

racemic mixture 194

195

196

3,4-trans, diastereomer of Ex197, less polar 197

3,4-trans, diastereomer of Ex196, more polar

TABLE 100 198

1′,2′-trans, 3,4-trans, diastereomer of Ex199, less polar 199

1′,2′-trans, 3,4-trans, diastereomer of Ex198, more polar 200

1′,2′-trans, 3,4-trans, diastereomer of Ex201, less polar 201

1′,2′-trans, 3,4-trans, diastereomer of Ex200, more polar 202

3,4-trans

TABLE 101 203

1′,2′-trans, 3,4-trans, diastereomer of Ex409 204

racemic mixture 205

1′,2′-trans, 3,4-trans, distereo mixture 206

3,4-trans, distereo mixture 207

3,4-trans, distereo mixture

TABLE 102 208

1′,2′-trans, 3,4-trans, distereomer of Ex209 209

1′,2′-trans, 3,4-trans, distereomer of Ex208 210

racemic mixture 211

3,4-trans, diastereomer of Ex212, less polar 212

3,4-trans, diastereomer of Ex211, more polar

TABLE 103 213

racemic mixture 214

215

216

racemic mixture 217

racemic mixture

TABLE 104 218

219

220

3,4-trans 221

racemic mixture 222

3,4-trans, diastereomer of Ex223, less polar

TABLE 105 223

3,4-trans, diastereomer of Ex222, more polar 224

1′,2′-trans, 3,4-trans 225

1′,2′-trans, 3,4-trans 226

racemic mixture, 1′,2′-cis, 3,4-trans 227

racemic mixture

TABLE 106 228

racemic mixture 229

racemic mixture 230

racemic mixture 231

racemic mixture

TABLE 107 232

racemic mixture 233

racemic mixture 234

racemic mixture 235

TABLE 108 236

237

238

racemic mixture 239

racemic mixture

TABLE 109 240

racemic mixture 241

racemic mixture 242

racemic mixture 243

racemic mixture

TABLE 110 244

racemic mixture 245

racemic mixture 246

racemic mixture 247

racemic mixture

TABLE 111 248

racemic mixture 249

racemic mixture 250

racemic mixture 251

racemic mixture

TABLE 112 252

racemic mixture 253

racemic mixture 254

racemic mixture 255

racemic mixture

TABLE 113 256

racemic mixture 257

258

racemic mixture 259

racemic mixture

TABLE 114 260

3,4-trans, diatereo mixture 261

racemic mixture 262

racemic mixture 263

racemic mixture

TABLE 115 264

racemic mixture 265

3,4-trans, diastereomer of Ex266, less polar 266

3,4-trans, diastereomer of Ex265, more polar 267

racemic mixture 268

racemic mixture

TABLE 116 269

racemic mixture 270

3,4-trans 271

diastereomer of Ex275, more polar 272

racemic mixture

TABLE 117 273

racemic mixture 274

racemic mixture 275

diastereomer of Ex271, less polar 276

racemic mixture 277

TABLE 118 278

279

racemic mixture 280

racemic mixture 281

racemic mixture

TABLE 119 282

racemic mixture 283

racemic mixture 284

3,4-trans, diatereo mixture 285

3,4-trans, diatereo mixture

TABLE 120 286

3,4-trans, diatereo mixture 287

3,4-trans, diastereo mixture 288

1′,2′-trans, 3,4-trans, diastereo mixture 289

1′,2′-trans, 3,4-trans, diastereomer of Ex290, more polar 290

racemic mixture, diastereomer of Ex289, less polar

TABLE 121 291

racemic mixture 292

racemic mixture 293

3,4-trans, diastereomer of Ex294, less polar 294

3,4-trans, diastereomer of Ex293, more polar

TABLE 122 295

racemic mixture 296

3,4-trans 297

racemic mixture 298

racemic mixture

TABLE 123 299

racemic mixture 300

racemic mixture 301

racemic mixture 302

racemic mixture, diastereomer of Ex306, less polar

TABLE 124 303

racemic mixture 304

racemic mixture 305

racemic mixture 306

racemic mixture, diastereomer of Ex302, more polar

TABLE 125 307

racemic mixture 308

racemic mixture 309

racemic mixture 310

racemic mixture

TABLE 126 311

racemic mixture 312

racemic mixture 313

racemic mixture 314

racemic mixture

TABLE 127 315

racemic mixture 316

racemic mixture 317

racemic mixture 318

racemic mixture

TABLE 128 319

racemic mixture 320

racemic mixture 321

racemic mixture 322

racemic mixture

TABLE 129 323

racemic mixture 324

racemic mixture 325

racemic mixture 326

racemic mixture

TABLE 130 327

racemic mixture 328

329

330

TABLE 131 331

racemic mixture 332

333

334

racemic mixture

TABLE 132 335

racemic mixture 336

racemic mixture 337

racemic mixture 338

racemic mixture

TABLE 133 339

racemic mixture 340

racemic mixture 341

racemic mixture 342

chiral compound, diastereomer of Ex343, less polar

TABLE 134 343

chiral compound, diastereomer of Ex342, more polar 344

racemic mixture 345

racemic mixture 346

racemic mixture

TABLE 135 347

racemic mixture 348

racemic mixture 349

racemic mixture 350

racemic mixture

TABLE 136 351

racemic mixture 352

racemic mixture 353

racemic mixture 354

racemic mixture

TABLE 137 355

racemic mixture 356

racemic mixture 357

racemic mixture 358

diastereo mixture

TABLE 138 359

360

racemic mixture 361

racemic mixture 362

racemic mixture

TABLE 139 363

racemic mixture 364

racemic mixture 365

racemic mixture 366

diastereo mixture

TABLE 140 367

racemic mixture 368

racemic mixture 369

racemic mixture 370

racemic mixture

TABLE 141 371

racemic mixture 372

racemic mixture 373

racemic mixture 374

racemic mixture

TABLE 142 375

racemic mixture, diastereomer of Ex377, more polar 376

racemic mixture 377

racemic mixture, diastereomer of Ex375, less polar 378

racemic mixture

TABLE 143 379

racemic mixture 380

racemic mixture 381

racemic mixture 382

TABLE 144 383

racemic mixture 384

385

386

chiral compound, diastereomer of Ex387, less polar

TABLE 145 387

chiral compound, diastereomer of Ex386, more polar 388

racemic mixture 389

racemic mixture 390

racemic mixture

TABLE 146 391

racemic mixture 392

racemic mixture 393

racemic mixture 394

racemic mixture

TABLE 147 395

racemic mixture 396

racemic mixture 397

racemic mixture 398

racemic mixture

TABLE 148 399

racemic mixture 400

401

402

1′,2′-trans, 3,4-trans, diastereomer of Ex404 403

racemic mixture

TABLE 149 404

1′,2′-trans, 3,4-trans, diastereomer of Ex402 405

racemic mixture 406

racemic mixture 407

408

TABLE 150 409

1′,2′-trans, 3,4-trans, diastereomer of Ex203 410

1′,2′-trans, 3,4-trans, diastereomer of Ex411, less polar 411

1′,2′-trans, 3,4-trans, diastereomer of Ex410, more polar 412

racemic mixture, 1′,2′-cis, 3,4-trans, diastereomer of Ex28 413

TABLE 151 414

1′,2′-trans, 3,4-trans 415

416

417

418

TABLE 152 419

420

1′,2′-cis, 3,4-trans, racemic mixture less polar 421

1′,2′-cis, 3,4-trans, racemic mixture more polar 422

racemic mixture 423

racemic mixture

TABLE 153 424

racemic mixture 425

426

427

racemic mixture 428

racemic mixture

TABLE 154 429

1′,2′-trans, 3,4-trans, diastereomer of Ex443, more polar 430

racemic mixture 431

432

racemic mixture 433

3,4-trans, diastereo mixture 434

3,4-trans, diastereo mixture

TABLE 155 435

racemic mixture 436

3,4-trans 437

racemic mixture 438

1′,2′-trans, 3,4-trans 439

racemic mixture

TABLE 156 440

1′,2′-cis, 3,4-trans, racemic mixture 441

1′,2′-trans, 3,4-trans, racemic mixture 442

1′,2′-trans, 3,4-trans 443

1′,2′-trans, 3,4-trans, diastereomer of Ex429, less polar 444

racemic mixture

TABLE 157 445

446

447

448

449

1′,2′-trans, 3,4-trans

TABLE 158 450

racemic mixture 451

racemic mixture 452

racemic mixture 453

1′,2′-cis, 3,4-trans, racemic mixture 454

1′,2′-cis, 3,4-trans, diastereomer of Ex455

TABLE 159 455

1′,2′-cis, 3,4-trans, racemic mixture 456

1′,2′-trans, 3,4-trans 457

1′,2′-trans, 3,4-trans, diastereomer of Ex456 458

3,4-trans 459

chiral compound, 3,4-trans

TABLE 160 460

racemic mixture 461

racemic mixture 462

racemic mixture

463

racemic mixture

TABLE 161 464

racemic mixture 465

racemic mixture 466

racemic mixture 467

TABLE 162 468

racemic mixture 469

racemic mixture 470

racemic mixture 471

racemic mixture

TABLE 163 472

racemic mixture 473

racemic mixture 474

racemic mixture 475

racemic mixture

TABLE 164 476

racemic mixture 477

racemic mixture 478

racemic mixture 479

racemic mixture

TABLE 165 480

racemic mixture 481

racemic mixture 482

racemic mixture 483

racemic mixture 484

racemic mixture

TABLE 166 485

racemic mixture 486

racemic mixture 487

racemic mixture 488

racemic mixture 489

racemic mixture

TABLE 167 490

racemic mixture 491

racemic mixture 492

racemic mixture 493

racemic mixture 494

racemic mixture

TABLE 168 495

racemic mixture 496

racemic mixture 497

racemic mixture 498

racemic mixture 499

racemic mixture

TABLE 169 500

racemic mixture 501

racemic mixture 502

racemic mixture 503

racemic mixture 504

racemic mixture

TABLE 170 505

racemic mixture 506

racemic mixture 507

racemic mixture  32

racemic mixture

TABLE 171 508

racemic mixture 509

racemic mixture 510

racemic mixture 511

racemic mixture 512

racemic mixture

TABLE 172 513

racemic mixture 514

racemic mixture 515

racemic mixture  33

racemic mixture 516

1′,2′-trans, 3,4-trans

TABLE 173 517

1′,2′-trans, 3,4-trans 518

1′,2′-trans, 3,4-trans, diastereomer of Ex519 519

1′,2′-trans, 3,4-trans, diastereomer of Ex518 520

1′,2′-trans, 3,4-trans

TABLE 174 521

1′,2′-trans, 3,4-trans 522

1′,2′-trans, 3,4-trans 523

1′,2′-trans, 3,4-trans 524

3,4-trans, racemic mixture

TABLE 175 525

3,4-trans 526

3,4-trans  35

racemic mixture 527

racemic mixture

TABLE 176 528

racemic mixture 529

530

racemic mixture 531

TABLE 177 532

racemic mixture 533

racemic mixture 534

racemic mixture 535

racemic mixture

TABLE 178 536

racemic mixture 537

racemic mixture 538

racemic mixture 539

racemic mixture

TABLE 179 540

racemic mixture 541

542

543

racemic mixture

TABLE 180 544

racemic mixture 545

racemic mixture 546

racemic mixture 547

racemic mixture

TABLE 181 548

racemic mixture 549

racemic mixture 550

racemic mixture 551

racemic mixture

TABLE 182 552

racemic mixture 553

racemic mixture 554

racemic mixture 555

TABLE 183 556

557

558

racemic mixture 559

racemic mixture

TABLE 184 560

561

racemic mixture 562

racemic mixture 563

racemic mixture

TABLE 185 564

racemic mixture 565

racemic mixture 566

racemic mixture 567

racemic mixture

TABLE 186 568

racemic mixture 569

racemic mixture 570

571

racemic mixture

TABLE 187 572

racemic mixture 573

3,4-trans racemic mixture 574

racemic mixture 575

racemic mixture

TABLE 188 576

racemic mixture 577

racemic mixture 578

3,4-trans  16

racemic mixture  15

racemic mixture

TABLE 189 22

racemic mixture 43

racemic mixture 29

racemic mixture

TABLE 190  23

racemic mixture  41

racemic mixture 579

racemic mixture  13

racemic mixture

TABLE 191 580

racemic mixture 581

racemic mixture, diastereomer of Ex582, less polar 582

racemic mixture, diastereomer of Ex581, more polar 583

racemic mixture

TABLE 192  14

racemic mixture 584

racemic mixture  12

racemic mixture 585

racemic mixture

TABLE 193 586

587

diastereomer of Ex594, less polar 588

racemic mixture 589

TABLE 194 590

racemic mixture 591

racemic mixture 592

racemic mixture 593

racemic mixture

TABLE 195 594

diastereomer of Ex587, more polar 595

racemic mixture 596

racemic mixture  18

racemic mixture

TABLE 196 597

racemic mixture 598

chiral compound, diastereomer of Ex599 599

chiral compound, diastereomer of Ex598 600

racemic mixture

TABLE 197  21

racemic mixture 601

racemic mixture  20

racemic mixture  27

1′,2′-trans, 3,4-trans

TABLE 198  40

racemic mixture 602

racemic mixture  8

racemic mixture 603

racemic mixture 604

1′,2′-trans, 3,4-trans, diastereomer of Ex605

TABLE 199 605

1′,2′-trans, 3,4-trans, diastereomer of Ex604 606

 6

racemic mixture 607

 42

racemic mixture

TABLE 200  31

racemic mixture 608

1′,2′-trans, 3,4-trans, diastereo mixture 609

racemic mixture 610

racemic mixture 611

1′,2′-trans, 3,4-trans, diastereomer of Ex616

TABLE 201 612

613

614

615

616

1′,2′-trans, 3,4-trans, diastereomer of Ex611 617

TABLE 202 618

619

racemic mixture 620

racemic mixture  5

racemic mixture 621

racemic mixture

TABLE 203  30

racemic mixture 622

racemic mixture 623

1′,2′-trans, 3,4-trans, diastereomer of Ex 624  28

1′,2′-cis, 3,4-trans 624

1′,2′-trans, 3,4-trans, diastereomer of Ex 623

TABLE 204  24

racemic mixture 625

racemic mixture 626

racemic mixture 627

racemic mixture

TABLE 205 628

racemic mixture 629

racemic mixture 630

racemic mixture 631

TABLE 206 632

racemic mixture 633

racemic mixture  19

racemic mixture 634

racemic mixture

TABLE 207 635

racemic mixture 636

racemic mixture  25

racemic mixture 637

racemic mixture

TABLE 208  26

racemic mixture  17-2

racemic mixture  17-1

3,4-trans 638

TABLE 209 639

640

racemic mixture  53

racemic mixture 641

racemic mixture

TABLE 210 642

racemic mixture  45

racemic mixture 643

racemic mixture

TABLE 211 644

racemic mixture 645

racemic mixture 646

racemic mixture 647

TABLE 212 648

649

650

racemic mixture 651

racemic mixture

TABLE 213  52

racemic mixture 652

racemic mixture 653

racemic mixture 654

TABLE 214 655

656

chiral compound, diastereomer of Ex 657, more polar 657

chiral compound, diastereomer of Ex 656, less polar  51

racemic mixture

TABLE 215 658

racemic mixture 659

chiral compound, diastereomer of Ex 667, more polar 660

racemic mixture 661

TABLE 216 662

663

664

racemic mixture 665

racemic mixture

TABLE 217 666

racemic mixture 667

chiral compound, diastereomer of Ex 659, less more 668

racemic mixture  46

racemic mixture

TABLE 218 669

racemic mixture 670

racemic mixture  47

racemic mixture

TABLE 219 671

racemic mixture 672

racemic mixture 673

racemic mixture

TABLE 220 674

racemic mixture 675

racemic mixture 676

racemic mixture 677

racemic mixture

TABLE 221 678

racemic mixture 679

680

681

racemic mixture

TABLE 222 682

racemic mixture 683

racemic mixture 684

racemic mixture  49

racemic mixture

TABLE 223 685

racemic mixture 686

racemic mixture 687

racemic mixture 688

racemic mixture

TABLE 224  55

racemic mixture 689

racemic mixture 690

racemic mixture 691

racemic mixture

TABLE 225 692

diastereo mixure, 1′,2′-trans, 3,4-trans 693

diastereo mixture, 1′,2′-trans, 3,4-trans  54

racemic mixture 694

racemic mixture

TABLE 226 695

racemic mixture 696

racemic mixture 697

racemic mixture 698

TABLE 227 699

racemic mixture 700

701

702

racemic mixture 703

racemic mixture

TABLE 228 704

racemic mixture 705

racemic mixture 706

707

racemic mixture 708

racemic mixture

TABLE 229  44

racemic mixture 709

710

711

racemic mixture

TABLE 230 712

713

racemic mixture 714

racemic mixture 715

TABLE 231  57

racemic mixture 716

racemic mixture 717

racemic mixture 718

TABLE 232 719

racemic mixture 720

racemic mixture 721

722

723

chiral compound, diastereomer of Ex724, more polar

TABLE 233 724

chiral compound, diastereomer of Ex723, less polar 725

racemic mixture 726

chiral compound, diastereomer of Ex727, less polar

TABLE 234 727

chiral compound, diastereomer of Ex726, more polar 728

racemic mixture 729

chiral compound, diastereomer of Ex733, more polar 730

racemic mixture

TABLE 235 731

racemic mixture 732

racemic mixture 733

chiral compound, diastereomer of Ex729, less polar

TABLE 236 734

chiral compound, diastereomer of Ex735, more polar 735

chiral compound, diastereomer of Ex734, less polar 736

chiral compound, diastereomer of Ex738, more polar

TABLE 237 737

chiral compound 738

chiral compound, diastereomer of Ex736, less polar 739

racemic mixture 740

racemic mixture

TABLE 238 741

racemic mixture 742

racemic mixture, diastereomer of Ex743, less polar 743

racemic mixture, diastereomer of Ex742, more polar 744

racemic mixture, diastereomer of Ex749, less polar 745

racemic mixture

TABLE 239 746

racemic mixture 747

racemic mixture 748

racemic mixture  59

TABLE 240 749

racemic mixture, diastereomer of Ex744, more polar 750

racemic mixture 751

diastero mixture, 1′,2′-trans, 3,4-trans 752

753

racemic mixture

TABLE 241 754

755

racemic mixture 756

chiral compound, diastereomer of Ex757, less polar 757

chiral compound, diastereomer of Ex756, more polar

TABLE 242 758

racemic mixture  50

chiral compound 759

760

TABLE 243 761

762

763

764

racemic mixture

TABLE 244 765

766

racemic mixture 767

racemic mixture 768

racemic mixture

TABLE 245 769

racemic mixture 770

771

racemic mixture 772

racemic mixture

TABLE 246 773

774

racemic mixture 775

776

racemic mixture

TABLE 247 777

racemic mixture  48

racemic mixture 778

779

TABLE 248 780

781

782

racemic mixture 783

chiral compound, diastereomer of Ex784, less polar

TABLE 249 784

chiral compound, diastereomer of Ex783, more polar 785

786

787

chiral compound

TABLE 250 788

racemic mixture 789

racemic mixture 790

791

792

TABLE 251 793

racemic mixture 794

diastereo mixure 795

chiral compound, diastereomer of Ex796, less polar

TABLE 252 796

chiral compound, diastereomer of Ex795, more polar 797

racemic mixture 798

chiral compound, diastereomer of Ex799, less polar 799

chiral compound, diastereomer of Ex798, more polar

TABLE 253 800

diastereo mixture 801

chiral compound 802

diastereo mixture 803

chiral compound

TABLE 254 804

racemic mixture 805

chiral compound  56

chiral compound 806

racemic mixture

TABLE 255 807

racemic mixture 808

racemic mixture 809

racemic mixture 810

chiral compound, diastereomer of Ex811, less polar

TABLE 256 811

chiral compound, diastereomer of Ex810, more polar 812

813

racemic mixture 814

chiral compound, diastereomer of Ex815, less polar

TABLE 257 815

chiral compound, diastereomer of Ex814, more polar 816

racemic mixture 817

818

TABLE 258 819

racemic mixture 820

racemic mixture 821

822

racemic mixture

TABLE 259 823

racemic mixture 824

racemic mixture 825

racemic mixture 826

racemic mixture

TABLE 260 827

racemic mixture 828

829

racemic mixture  58

TABLE 261 830

racemic mixuture, 1′,2′-trans, 3,4-trans, diastereomer of Ex831, more polar 831

racemic mixuture, 1′,2′-trans, 3,4-trans 832

chiral compound, diastereomer of Ex833, less polar 833

chiral compound, diastereomer of Ex832, more polar 834

racemic mixture

TABLE 262 835

diastereo mixture 836

racemic mixture 837

racemic mixture 838

racemic mixture 839

racemic mixture

TABLE 263 840

racemic mixture 841

diastereo mixture 842

diastereo mixture 843

TABLE 264 844

racemic mixture 845

846

racemic mixture 847

chiral compound, 3,4-trans 848

racemic mixture, diastereomer of Ex849, less polar

TABLE 265 849

racemic mixture, diastereomer of Ex848, more polar 850

racemic mixture, diastereomer of Ex851, less polar 851

racemic mixture, diastereomer of Ex850, more polar 852

853

racemic mixture

TABLE 266 854

chiral compound, diastereomer of Ex855, less polar 855

chiral compound, diastereomer of Ex854, more polar 856

857

racemic mixture 858

racemic mixture

TABLE 267 859

racemic mixture 860

racemic mixture, 1′,2′-trans, 3,4-trans 861

racemic mixure, 1′,2′-trans, 3,4-trans 862

racemic mixture 863

racemic mixture, 1′,2′-trans, 3,4-trans 864

racemic mixture

TABLE 268 865

racemic mixture, 1′,2′-trans, 3,4-trans 866

racemic mixture, diastereomer of Ex872, 1′,2′-trans, 3,4-trans 867

racemic mixture, 1′,2′-trans, 3,4-trans 868

racemic mixture 869

racemic mixture, 1′,2′-trans, 3,4-trans

TABLE 269 870

racemic mixture, 1′,2′-trans, 3,4-trans 871

racemic mixture, diastereomer of Ex863, 1′,2′-trans, 3,4-trans 872

racemic mixture, diastereomer of Ex866, 1′,2′-trans, 3,4-trans 873

racemic mixture, 1′,2′-trans, 3,4-trans 874

1′,2′-trans, 3,4-trans

TABLE 270 875

1′,2′-trans, 3,4-trans 876

877

878

racemic mixture

TABLE 271 879

racemic mixture 880

881

racemic mixture 882

racemic mixture 883

racemic mixture

TABLE 272 884

885

racemic mixture 886

887

racemic mixture 888

TABLE 273 889

racemic mixture 890

891

892

TABLE 274 893

racemic mixture 894

racemic mixture 895

less polar, diastereomer of Ex896 896

more polar, diastereomer of Ex895

TABLE 275 897

racemic mixture 898

racemic mixture 899

racemic mixture

TABLE 276 Ex Syn Data 60 1 FAB+: 573 61 1 FAB+: 574 62 1 FAB+: 559 63 1 FAB+: 537 64 3 FAB+: 590 65 1 FAB+: 548 66 1 ESI+: 537 67 1 FAB+: 537 68 1 FAB+: 573 69 1 FAB+: 544 70 1 FAB+: 519 71 1 FAB+: 533 72 1 FAB+: 508 73 1 FAB+: 523 74 5 FAB+: 536 75 6 FAB+: 564 1 1 FAB+: 507 76 1 FAB+: 508 77 1 FAB+: 521 78 1 FAB+: 525 3 3 ESI+: 524 79 1 FAB+: 525 80 1 FAB+: 503 81 1 FAB+: 565 82 1 FAB+: 511 83 1 FAB+: 467 84 1 ESI+: 499 85 1 FAB+: 491 86 1 FAB+: 539 37 37 FAB+: 560 87 1 FAB+: 533 88 1 FAB+: 503 89 1 FAB+: 511 90 1 FAB+: 525 91 1 FAB+: 483

TABLE 277 92 1 FAB+: 513 93 1 FAB+: 483 94 1 FAB+: 548 95 5 FAB+: 522 96 1 FAB+: 567 97 1 FAB+: 538 98 1 FAB+: 475 99 1 FAB+: 499 100 1 FAB+: 491 101 1 FAB+: 499 102 1 FAB+: 559 103 6 FAB+: 550 104 3 FAB+: 524 105 1 FAB+: 503 106 1 FAB+: 499 107 1 FAB+: 497 108 1 FAB+: 565 2 2 FAB+: 507 109 39 FAB+: 497 39 39 FAB+: 511 110 1 FAB+: 391 111 1 FAB+: 431 4 4 FAB+: 475 112 1 FAB+: 573 113 32 FAB+: 488 114 32 FAB+: 474 115 38 FAB+: 407 116 33 FAB+: 420 117 33 FAB+: 434 118 1 FAB+: 573 119 1 FAB+: 514 120 1 FAB+: 516 121 1 FAB+: 529 122 1 FAB+: 440 123 1 FAB+: 440 124 1 FAB+: 440

TABLE 278 36 36 FAB+: 456 125 36 FAB+: 456 126 36 FAB+: 456 127 1 FAB+: 497 38 38 FAB+: 483 128 38 FAB+: 483 7 7 FAB+: 393 129 1 FAB+: 467 130 10 FAB+: 498 10 10 FAB+: 604 131 10 FAB+: 527 132 3 ESI+: 633 133 3 ESI+: 617 134 3 ESI+: 617 135 3 ESI+: 645 136 3 ESI+: 617 137 3 FAB+: 647 138 3 ESI+: 663 139 3 ESI+: 647 140 3 ESI+: 651 141 3 ESI+: 633 142 3 ESI+: 633 143 3 ESI+: 667 144 3 FAB+: 647 145 3 ESI+: 655 146 3 ESI+: 631 147 3 ESI+: 633 NMR1: 1.00-1.90 (7H, m), 2.06-2.23 (1H, m), 2.92 (3H, s), 3.25-3.45 (1H, m), 3.60 (1H, s), 4.12 (1H, brs), 4.90-5.06 (2H, m), 5.21 (1H, s), 6.39 (1H, brs), 6.89 (1H, d, J = 8.4 Hz), 7.04-7.20 (2H, m), 7.27-7.69 (6H, m), 7.87-7.97 (1H, m), 8.29 (1H, d, J = 6.4 Hz), 11.64 (1H, brs) 9 9 FAB+: 517 148 11 FAB+: 580 149 11 FAB+: 580 11 11 FAB+: 581 150 1 ESI−: 635 151 1 FAB+: 550 152 1 FAB+: 589 153 1 FAB+: 582 154 1 FAB+: 561

TABLE 279 155 1 FAB+: 561 156 1 FAB+: 563 157 1 FAB+: 563 NMR1: 1.19 (3H, d, J = 6.0 Hz), 3.10-3.40 (2H, m), 3.54 (1H, s), 3.99-4.12 (1H, m), 4.34 (1H, brs), 4.46-4.58 (1H, m), 4.80 (2H, brs), 4.90 (1H, brs), 5.75 (1H, s), 6.79 (1H, d, J = 8.4 Hz), 6.99-7.08 (1H, m), 7.17 (1H, d, J = 8.4 Hz), 7.31-7.51 (6H, m), 7.61 (1H, s), 7.96-8.09 (1H, m), 11.63 (1H, brs) 158 1 FAB+: 523 159 1 FAB+: 498 160 1 FAB+: 498 161 1 FAB+: 555 162 1 FAB+: 551 163 1 FAB+: 552 164 1 FAB+: 538 165 1 FAB+: 636 166 1 FAB+: 579 167 1 FAB+: 482 168 1 FAB+: 536 169 1 FAB+: 510 170 1 FAB+: 540 171 1 FAB+: 553 172 1 FAB+: 578 173 1 FAB+: 552 174 1 FAB+: 583 175 1 FAB+: 565 176 1 FAB+: 579 177 1 FAB+: 549 178 1 FAB+: 538 34 34 FAB+: 647 179 1 FAB+: 551 180 1 FAB+: 664 181 1 FAB+: 555 182 1 FAB+: 539 183 1 FAB+: 555 184 1 FAB+: 540 185 1 FAB+: 668 186 1 FAB+: 668 187 1 FAB+: 547 188 1 FAB+: 540 189 1 FAB+: 505

TABLE 280 190 1 FAB+: 505 191 1 FAB+: 499 192 1 FAB+: 499 193 1 FAB+: 533 194 1 FAB+: 528 195 1 ESI+: 528 196 1 ESI+: 561 197 1 ESI+: 559 198 1 FAB+: 505 199 1 FAB+: 505 200 1 FAB+: 594 201 1 FAB+: 594 202 1 FAB+: 597 203 1 FAB+: 527 204 1 ESI+: 534 205 1 FAB+: 626 206 1 FAB+: 610 207 1 FAB+: 610 208 1 FAB+: 682 209 1 FAB+: 682 210 1 FAB+: 539 211 1 ESI+: 515 212 1 ESI+: 515 213 1 FAB+: 533 214 1 ESI−: 541 215 1 ESI−: 541 NMR1: 1.16 (3H, d, J = 6.0 Hz), 2.54-2.64 (2H, m), 3.09-3.38 (4H, m), 3.77 (1H, s), 3.99-4.11 (1H, m), 4.27-4.37 (1H, m), 4.52 (1H, brs), 5.13 (1H, d, J = 4.4 Hz), 5.70 (1H, s), 6.65 (2H, d, J = 8.4 Hz), 6.81 (1H, d, J = 8.4 Hz), 6.94 (2H, d, J = 8.4 Hz), 7.11-7.24 (2H, m), 7.36-7.49 (2H, m), 7.60 (1H, d, J = 2.0 Hz), 7.95-8.08 (1H, m), 8.35-8.50 (1H, m), 9.17 (1H, s) 216 1 FAB+: 632 217 1 FAB+: 533 218 1 FAB+: 538 219 1 FAB+: 538 NMR1: 1.54-1.71 (1H, m), 1.76-1.90 (1H, m), 1.96-2.21 (2H, m), 3.01-3.24 (2H, m), 3.27-3.40 (1H, m), 3.55 (1H, brs), 3.70 (1H, s), 4.70-4.80 (2H, m), 5.25 (1H, s), 7.10-7.18 (1H, m), 7.22 (1H, dd, J = 2.4, 8.4 Hz), 7.30-7.47 (7H, m), 7.52 (1H, d, J = 8.4 Hz), 7.62 (1H, d, J = 2.0 Hz), 7.82-7.90 (1H, m), 11.34 (1H, s)

TABLE 281 220 1 FAB+: 610 221 1 FAB+: 573 222 1 FAB+: 529 223 1 ESI−: 527 224 1 ESI+: 541 225 1 FAB+: 561 226 1 FAB+: 616 227 1 FAB+: 549 228 1 FAB+: 664 229 1 FAB+: 679 230 1 FAB+: 679 231 1 FAB+: 602 232 1 ESI+: 680 233 1 ESI+: 694 234 1 FAB+: 678 235 1 ESI+: 674 236 1 FAB+: 614 237 1 FAB+: 614 238 1 FAB+: 693 239 1 FAB+: 659 240 1 FAB+: 587 241 1 FAB+: 694 242 1 FAB+: 587 243 1 ESI+: 675 244 1 FAB+: 670 245 1 ESI+: 602 246 1 ESI+: 607 247 1 ESI+: 672 248 R381 ESI+: 574 249 R381 FAB+: 573 250 1 FAB+: 567 251 1 FAB+: 566 252 1 ESI+: 658 253 1 ESI+: 658 254 1 FAB+: 632 255 1 FAB+: 585 256 1 FAB+: 584 257 1 FAB+: 674 258 1 ESI+: 658

TABLE 282 259 1 FAB+: 630 260 1 FAB+: 639 261 1 ESI+: 603 262 1 FAB+: 600 263 1 FAB+: 607 264 1 FAB+: 628 265 1 FAB+: 616 266 1 FAB+: 616 267 1 ESI+: 603 268 1 ESI+: 631 269 1 FAB+: 629 270 1 FAB+: 617 271 1 FAB+: 577 272 1 FAB+: 554 273 1 ESI+: 601 274 1 FAB+: 601 275 1 FAB+: 577 276 1 ESI+: 602 277 1 ESI+: 539 278 1 ESI+: 539 279 1 FAB+: 601 280 1 ESI+: 554 281 1 FAB+: 624 282 1 ESI−: 626 283 1 FAB+: 582 284 1 ESI+: 593 285 1 ESI+: 593 286 1 FAB+: 592 287 1 FAB+: 592 288 1 FAB+: 498 289 1 FAB+: 530 290 1 FAB+: 530 291 1 FAB+: 704 292 1 FAB+: 502 293 1 FAB+: 529 294 1 ESI−: 527 295 1 FAB+: 638 296 1 FAB+: 630 297 1 FAB+: 633 298 1 FAB+: 744 299 1 FAB+: 746

TABLE 283 300 1 ESI+: 718 301 1 FAB+: 730 302 1 FAB+: 647 303 1 ESI+: 633 304 1 FAB+: 751 305 1 ESI+: 688 306 1 ESI+: 647 307 1 ESI+: 723 308 1 FAB+: 730 309 1 FAB+: 652 310 1 FAB+: 638 311 1 FAB+: 710 312 1 ESI+: 849 313 1 ESI+: 660 314 1 ESI+: 673 315 1 FAB+: 647 316 1 FAB+: 647 317 1 ESI+: 730 318 1 ESI+: 656 319 1 FAB+: 730 320 1 ESI+: 728 321 1 ESI+: 618 322 1 FAB+: 688 323 1 FAB+: 692 324 1 FAB+: 704 325 1 FAB+: 704 326 1 FAB+: 634 327 1 FAB+: 702 328 1 FAB+: 617 329 1 ESI+: 674 330 1 FAB+: 680 331 1 FAB+: 635 332 1 FAB+: 608 333 1 ESI+: 688 334 1 FAB+: 622 335 1 ESI+: 631 336 1 FAB+: 617 337 1 FAB+: 617 338 1 ESI+: 660 339 1 FAB+: 635 340 1 ESI+: 622

TABLE 284 341 1 FAB+: 647 342 1 FAB+: 563 343 1 FAB+: 563 344 1 FAB+: 635 345 1 ESI+: 660 346 1 FAB+: 631 347 1 ESI+: 622 348 1 ESI+: 647 349 1 ESI+: 673 350 1 ESI+: 606 351 1 FAB+: 620 352 1 ESI+: 632 353 1 FAB+: 619 354 1 ESI−: 568 355 1 FAB+: 620 356 1 FAB+: 642 357 1 FAB+: 622 358 1 ESI+: 631 359 1 ESI+: 680 360 1 ESI+: 565 361 1 FAB+: 607 362 1 ESI+: 591 363 1 ESI+: 642 364 1 FAB+: 613 365 1 ESI+: 651 366 1 FAB+: 657 367 1 FAB+: 637 368 1 FAB+: 631 369 1 ESI+: 637 370 1 FAB+: 623 371 1 FAB+: 631 372 1 ESI+: 618 373 1 ESI+: 688 374 1 FAB+: 631 375 1 FAB+: 601 376 1 FAB+: 702 377 1 FAB+: 601 378 1 ESI+: 647 379 1 ESI+: 643 380 1 FAB+: 654 381 1 ESI+: 602

TABLE 285 382 1 FAB+: 630 383 1 FAB+: 657 384 1 FAB+: 587 385 1 FAB+: 587 386 1 FAB+: 630 387 1 FAB+: 630 388 1 FAB+: 631 389 1 FAB+: 671 390 1 ESI+: 679 391 1 FAB+: 640 392 1 ESI+: 647 393 1 FAB+: 608 394 1 ESI+: 643 395 1 FAB+: 660 396 1 ESI+: 602 397 1 ESI+: 602 398 1 ESI+: 640 399 1 ESI+: 641 400 1 FAB+: 538 401 1 FAB+: 538 NMR1: 1.54-1.71 (1H, m), 1.75-1.89 (1H, m), 1.97-2.21 (2H, m), 2.99-3.25 (2H, m), 3.26-3.41 (1H, m), 3.55 (1H, brs), 3.70 (1H, s), 4.67-4.82 (2H, m), 5.25 (1H, s), 7.10-7.18 (1H, m), 7.22 (1H, dd, J = 2.4, 8.4 Hz), 7.27-7.40 (7H, m), 7.52 (1H, d, J = 8.4 Hz), 7.62 (1H, d, J = 2.0 Hz), 7.80-7.90 (1H, m), 11.34 (1H, s) 402 1 ESI+: 528 403 1 FAB+: 547 404 1 ESI+: 528 405 1 FAB+: 569 406 1 FAB+: 582 407 1 FAB+: 529 408 1 FAB+: 529 409 1 FAB+: 527 410 1 FAB+: 539 411 1 FAB+: 539 412 1 ESI−: 593 413 1 FAB+: 540 414 1 FAB+: 668 415 1 FAB+: 540 416 1 FAB+: 592 417 1 FAB+: 592

TABLE 286 418 1 FAB+: 592 419 1 FAB+: 592 420 1 FAB+: 537 421 1 FAB+: 537 422 1 FAB+: 551 423 1 FAB+: 540 424 1 FAB+: 539 425 1 FAB+: 587 426 1 FAB+: 575 427 1 FAB+: 566 428 1 FAB+: 551 429 1 FAB+: 530 430 1 FAB+: 510 431 1 FAB+: 538 432 1 FAB+: 508 433 1 FAB+: 608 434 1 FAB+: 538 435 1 FAB+: 601 436 1 FAB+: 587 437 1 FAB+: 613 438 1 FAB+: 674 439 1 FAB+: 539 440 1 FAB+: 593 441 1 FAB+: 500 442 1 FAB+: 499 443 1 FAB+: 530 444 1 FAB+: 540 445 1 FAB+: 530 446 1 FAB+: 530 447 1 FAB+: 530 448 1 FAB+: 530 449 1 FAB+: 596 450 1 FAB+: 540 451 1 ESI+: 515 452 1 FAB+: 540 453 1 FAB+: 596 454 1 ESI+: 595 455 1 ESI+: 595 456 1 ESI+: 595 457 1 ESI+: 595 458 1 FAB+: 571

TABLE 287 459 1 FAB+: 571 460 1 FAB+: 538 461 1 FAB+: 605 462 1 ESI+: 618 463 1 ESI+: 606 464 1 ESI+: 746 465 1 ESI+: 690 466 1 ESI+: 703 467 1 ESI+: 692 468 1 ESI+: 746 469 1 ESI+: 732 470 1 ESI+: 718 471 1 ESI+: 692 472 1 ESI+: 692 473 1 FAB+: 642 474 1 ESI+: 732 475 1 ESI+: 606 476 1 ESI+: 746 477 1 FAB+: 618 478 1 ESI+: 638 479 1 ESI+: 692 480 1 ESI+: 605 481 1 FAB+: 543 482 1 ESI+: 557 483 1 FAB+: 571 484 1 FAB+: 674 485 1 ESI+: 674 486 1 FAB+: 597 487 1 FAB+: 553 488 1 FAB+: 597 489 1 FAB+: 589 490 1 FAB+: 576 491 1 FAB+: 567 492 1 FAB+: 545 493 1 FAB+: 546 494 1 ESI−: 567 495 1 FAB+: 567 496 1 FAB+: 567 497 1 FAB+: 607 498 1 FAB+: 553 499 1 ESI+: 573

TABLE 288 500 1 FAB+: 573 501 1 ESI+: 592 502 1 FAB+: 603 503 1 ESI+: 565 504 1 FAB+: 565 505 1 FAB+: 573 506 1 FAB+: 505 507 1 ESI+: 557 32 32 FAB+: 623 508 32 FAB+: 595 509 32 ESI+: 659 510 32 FAB+: 610 511 32 ESI+: 582 512 32 ESI+: 596 513 32 FAB+: 610 514 32 FAB+: 582 515 32 FAB+: 596 33 33 FAB+: 496 516 34 FAB+: 581 517 34 FAB+: 567 518 34 FAB+: 595 519 34 FAB+: 595 520 34 FAB+: 611 521 34 FAB+: 637 522 34 FAB+: 638 523 34 FAB+: 650 524 34 FAB+: 596 525 34 FAB+: 609 526 34 ESI−: 627 35 35 FAB+: 596 527 35 FAB+: 623 528 4 ESI+: 674 529 4 ESI−: 571 NMR1: 1.19 (3H, d, J = 6.0 Hz), 3.12-3.48 (2H, m), 3.55 (1H, s), 4.01-4.13 (1H, m), 4.28-4.38 (1H, m), 4.47-4.60 (1H, m), 4.80-4.97 (3H, m), 5.73 (1H, s), 6.79 (1H, d, J = 8.4 Hz), 7.01-7.09 (1H, m), 7.17 (1H, dd, J = 2.0, 8.4 Hz), 7.39-7.69 (5H, m), 7.91-8.08 (3H, m), 11.67 (1H, s), 13.04 (1H, brs) 530 4 ESI+: 661 531 4 ESI−: 571 532 4 FAB+: 644

TABLE 289 533 4 ESI+: 666 534 4 ESI+: 666 535 4 ESI+: 665 536 4 ESI+: 645 537 4 FAB+: 688 538 4 ESI+: 688 539 4 ESI+: 690 540 4 ESI+: 674 541 4 ESI+: 674 NMR1: 1.00-2.30 (8H, m), 2.94 (3H, s), 3.58 (3H, s), 4.07 (1H, brs), 4.74 (1H, d, J = 11.0 Hz), 4.77 (1H, d, J = 11.0 Hz), 5.18 (1H, s), 6.36 (1H, d, J = 6.9 Hz), 6.88 (1H, d, J = 8.4 Hz), 7.08-7.11 (1H, m), 7.16 (1H, d, J = 2.0 Hz), 7.18 (1H, d, J = 2.0 Hz), 7.26 (2H, d, J = 8.0 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.43-7.48 (2H, m), 7.64 (1H, d, J = 2.0 Hz) 7.93-7.96 (1H, m), 11.42 (1H, s), 12.34 (1H, brs) 542 4 FAB+: 710 NMR1: 0.48-0.71 (1H, m), 1.01-1.37 (4H, m), 1.40-1.65 (2H, m), 2.46-2.59 (1H, m), 2.78 (3H, s), 3.15-3.50 (2H, m), 4.66-4.84 (3H, m), 5.17 (1H, s), 6.68 (1H, d, J = 8.4 Hz), 7.02-7.09 (1H, m), 7.12-7.20 (3H, m), 7.27-7.40 (2H, m), 7.46 (1H, d, J = 0.8 Hz), 7.64 (1H, d, J = 8.0 Hz), 8.57 (1H, brs) 543 4 ESI+: 718 544 4 ESI+: 702 545 4 ESI−: 702 546 4 FAB+: 638 547 4 FAB+: 624 548 4 ESI+: 702 549 4 ESI+: 676 550 4 ESI+: 674 551 4 ESI+: 640 552 4 ESI+: 678 553 4 ESI−: 688 554 4 ESI+: 690 555 4 FAB+: 660 556 4 ESI+: 660 557 4 ESI+: 666 558 4 FAB+: 620 559 4 ESI+: 596 560 4 ESI+: 660 561 4 FAB+: 583 562 4 ESI+: 583

TABLE 290 563 4 ESI+: 660 564 4 ESI+: 660 565 4 ESI+: 678 566 4 FAB+: 678 567 4 ESI+: 690 568 4 FAB+: 718 569 4 ESI+: 647 570 4 ESI+: 678 571 4 FAB+: 678 572 38 FAB+: 592 573 39 ESI+: 569 574 39 ESI+: 582 575 39 ESI+: 602 576 39 FAB+: 565 577 39 FAB+: 636 578 39 FAB+: 573 16 16 FAB+: 579 15 15 ESI−: 579 22 22 ESI+: 716 43 43 FAB+: 680 29 29 ESI+: 666 23 23 ESI+: 700 41 41 FAB+: 624 579 23 ESI+: 830 13 13 FAB+: 617 580 13 FAB+: 609 581 13 FAB+: 577 582 13 FAB+: 577 583 13 FAB+: 618 14 14 FAB+: 645 584 12 FAB+: 576 12 12 FAB+: 616 585 12 FAB+: 617 586 12 ESI+: 617 587 12 FAB+: 608 588 12 FAB+: 678 589 12 ESI+: 617 590 12 FAB+: 615 591 12 FAB+: 562 592 12 FAB+: 630 593 12 FAB+: 616

TABLE 291 594 12 FAB+: 608 595 12 FAB+: 580 596 12 FAB+: 610 18 18 ESI+: 684 597 18 FAB+: 592 598 18 ESI+: 606 599 18 ESI+: 606 600 18 ESI+: 608 21 21 ESI+: 598 601 21 ESI+: 674 20 20 ESI+: 737 27 27 FAB+: 593 40 40 ESI−: 568 602 40 FAB+: 569 8 8 FAB+: 577 603 6 FAB+: 566 604 6 FAB+: 540 605 6 FAB+: 540 606 6 FAB+: 524 6 6 FAB+: 564 607 6 FAB+: 524 42 42 ESI+: 648 31 31 FAB+: 638 608 5 ESI+: 526 609 5 ESI+: 484 610 5 FAB+: 538 611 5 FAB+: 582 612 5 ESI+: 510 613 5 ESI+: 510 614 5 ESI+: 510 615 5 ESI+: 510 616 5 FAB+: 582 617 5 FAB+: 508 618 5 FAB+: 508 619 5 FAB+: 536 620 5 FAB+: 536 5 5 FAB+: 482 621 5 FAB+: 538 30 30 FAB+: 632 622 30 ESI+: 648 623 28 FAB+: 568

TABLE 292 28 28 FAB+: 568 624 28 FAB+: 568 24 24 ESI+: 607 625 19 ESI+: 632 626 19 FAB+: 674 627 19 ESI+: 672 628 19 ESI+: 688 629 19 FAB+: 654 630 19 FAB+: 674 631 19 ESI+: 690 632 19 ESI+: 584 633 19 ESI+: 613 19 19 ESI+: 690 634 19 ESI+: 647 635 19 ESI+: 632 636 19 FAB+: 690 25 25 ESI+: 633 637 25 FAB+: 690 26 26 FAB+: 526 17-2 17 FAB+: 568 17-1 17 FAB+: 550 638 1 ESI+: 724 639 1 ESI+: 780 640 53 ESI+: 650 53 53 ESI+: 664 641 30 ESI+: 648 642 1 ESI+: 662 45 45 ESI+: 632 643 4 ESI+: 676 644 1 ESI+: 623 645 1 ESI+: 748 646 1 ESI+: 704 647 1 ESI+: 688 648 1 FAB+: 676 4 649 1 ESI+: 690 4 650 4 FAB+: 718 651 3 FAB+: 767 52 52 ESI+: 663

TABLE 293 652 19 ESI+: 648 653 1 FAB+: 611 19 654 4 ESI+: 674 655 1 ESI+: 674 4 656 1 FAB+: 615 657 1 FAB+: 615 51 51 ESI+: 598 658 1 FAB+: 665 659 3 ESI+: 631 660 1 ESI+: 695 661 43 ESI+: 624 662 41 ESI+: 680 663 55 ESI+: 638 664 20 ESI+: 767 665 6 ESI+: 703 12 666 4 ESI+: 651 667 3 ESI+: 631 668 39 ESI+: 675 46 46 FAB+: 660 669 1 FAB+: 673 670 1 ESI+: 721 47 47 ESI+: 624 671 1 ESI+: 704 672 1 FAB+: 672 673 1 ESI+: 731 674 1 ESI+: 710 19 675 19 ESI+: 648 676 19 FAB+: 675 677 1 ESI+: 695 678 1 ESI+: 735 679 1 ESI+: 710 19 680 1 ESI+: 688 19 681 P8 ESI−: 675 P9 1

TABLE 294 682 1 FAB+: 658 683 4 ESI+: 663 684 1 FAB+: 611 49 49 FAB+: 689 685 3 FAB+: 705 686 4 FAB+: 597 687 1 FAB+: 633 688 1 ESI+: 731 55 55 FAB+: 663 689 1 FAB+: 703 690 20 FAB+: 674 691 19 ESI+: 675 692 1 ESI+: 744 693 19 ESI+: 688 54 54 ESI+: 663 694 3 FAB+: 719 695 1 FAB+: 752 696 P38 ESI+: 714 1 697 54 FAB+: 679 698 52 ESI+: 648 699 4 FAB+: 700 700 1 ESI+: 735 NMR1: 0.99-1.85 (8H, m), 2.10-2.24 (1H, m), 2.69-2.83 (2H, m), 2.92 (3H, s), 3.25-3.45 (5H, m), 3.73 (1H, s), 3.95 (1H, brs), 5.21 (1H, s), 6.41-6.51 (1H, m), 6.85 (1H, d, J = 8.0 Hz), 7.11-7.22 (2H, m), 7.35-7.48 (4H, m), 7.64 (1H, d, J = 2.0 Hz), 7.73-7.81 (2H, m), 7.88-7.96 (1H, m), 8.07 (1H, brs), 12.08 (1H, brs) 701 19 ESI+: 672 NMR1: 0.99-1.87 (8H, m), 2.11-2.26 (1H, m), 2.59-2.74 (2H, m), 2.91 (3H, s), 3.18-3.40 (2H, m), 3.51 (2H, s), 3.75 (1H, s), 3.93 (1H, brs), 5.24 (1H, s), 6.41-6.54 (1H, m), 6.85 (1H, d, J = 8.0 Hz), 7.01-7.23 (6H, m), 7.39-7.48 (2H, m), 7.65 (1H, d, J = 2.0 Hz), 7.89- 7.98 (1H, m), 8.08 (1H, brs), 12.28 (1H, brs) 702 19 FAB+: 595 703 4 FAB+: 589 704 1 ESI+: 669 705 1 FAB+: 555 706 1 ESI+: 746 707 1 FAB+: 531 708 1 ESI+: 678

TABLE 295 44 44 ESI−: 650 709 4 FAB+: 718 NMR1: 1.09 (2H, t, J = 6.9 Hz), 1.00-2.00 (5H, m), 2.10-2.25 (1H, m), 2.40 (2H, t, J = 7.2 Hz), 2.94 (3H, s), 3.18-3.50 (3H, m), 3.57 (1H, s), 3.98 (1H, t, J = 6.3 Hz), 4.73 (1H, d, J = 11.3 Hz), 4.78 (1H, d J = 11.3 Hz), 5.16 (1H, s), 6.32-6.38 (1H, m), 6.85-6.95 (3H, m), 7.05-7.50 (3H, m), 7.39-7.48 (2H, m), 7.63 (1H, d, J = 2.0 Hz), 7.89-7.98 (1H, m), 11.39 (1H, brs) 710 1 ESI+: 751 711 19 ESI+: 708 712 19 ESI+: 708 NMR1: 0.99-1.87 (8H, m), 2.11-2.26 (1H, m), 2.59-2.74 (2H, m), 2.91 (3H, s), 3.18-3.40 (2H, m), 3.51 (2H, s), 3.75 (1H, s), 3.93 (1H, brs), 5.24 (1H, s), 6.41- 6.54 (1H, m), 6.85 (1H, d, J = 8.0 Hz), 7.01-7.23 (6H, m), 7.39-7.48 (2H, m), 7.65 (1H, d, J = 2.0 Hz), 7.89-7.98 (1H, m), 8.08 (1H, brs), 12.28 (1H, brs) 713 19 ESI+: 631 714 19 ESI+: 633 715 3 ESI+: 767 57 57 ESI+: 701 716 4 FAB+: 650 717 32 ESI+: 596 718 52 ESI+: 663 719 1 FAB+: 596 720 1 ESI+: 572 721 4 ESI+: 641 722 32 FAB+: 610 723 21 ESI+: 596 724 21 FAB+: 596 725 1 FAB+: 751 726 1 ESI+: 639 727 1 ESI+: 639 728 P9  ESI+: 617 P40 1 729 41 ESI+: 622 730 52 ESI+: 647 731 3 FAB+: 767 732 52 FAB+: 663 733 41 ESI+: 622 734 18 ESI+: 682 735 18 ESI+: 682

TABLE 296 736 21 ESI+: 672 737 41 ESI+: 698 738 21 ESI+: 672 739 4 ESI+: 589 740 44 ESI−: 650 741 1 ESI+: 782 742 1 ESI+: 538 743 1 ESI+: 538 744 3 ESI+: 554 745 44 ESI−: 573 746 1 ESI+: 555 747 1 ESI+: 563 748 21 ESI+: 596 59 59 ESI+: 681 749 3 ESI+: 554 750 41 ESI+: 622 751 19 ESI−: 623 752 19 FAB+: 710 753 19 ESI+: 633 754 19 ESI+: 708 755 19 ESI+: 631 756 1 ESI+: 645 757 1 ESI+: 645 758 1 ESI+: 644 50 50 ESI+: 687 759 1 ESI+: 731 760 1 ESI+: 706 761 19 ESI−: 609 762 19 FAB+: 675 763 19 ESI+: 650 764 1 ESI+: 709 765 1 ESI−: 656 766 1 ESI+: 678 767 44 ESI+: 667 768 4 FAB+: 664 769 44 ESI+: 650 770 1 ESI+: 720 771 1 ESI+: 643 772 19 ESI+: 587 773 19 ESI+: 664 774 1 ESI+: 779

TABLE 297 775 1 ESI+: 706 776 P8 ESI+: 633 P9 1 777 35 ESI+: 597 48 48 ESI+: 689 778 19 ESI+: 650 779 1 FAB+: 633 780 1 ESI+: 661 781 4 ESI+: 619 782 1 ESI−: 577 783 1 ESI+: 631 784 1 ESI+: 631 785 48 ESI+: 601 786 48 ESI+: 601 787 1 ESI+: 672 19 788 21 ESI+: 612 789 3 ESI+: 613 790 4 ESI+: 647 791 19 ESI+: 617 792 19 ESI+: 617 793 P9 ESI+: 678 1 794 1 ESI+: 714 795 19 ESI+: 658 796 19 ESI+: 658 797 41 ESI+: 638 798 1 ESI+: 562 799 1 ESI+: 562 800 1 FAB+: 744 801 19 ESI+: 688 802 1 ESI+: 667 803 19 ESI+: 611 804 44 ESI−: 634 805 3 ESI+: 703 56 56 ESI: 661 806 4 ESI+: 650 807 44 ESI+: 636 808 19 ESI+: 658 809 19 ESI+: 581

TABLE 298 810 1 ESI+: 671 811 1 ESI+: 671 812 1 ESI−: 718 813 P23 ESI−: 641 1 814 1 ESI+: 687 815 1 ESI+: 687 816 19 ESI+: 587 817 19 ESI+: 664 818 P23 ESI+: 744 1 819 1 ESI+: 667 820 19 ESI+: 611 821 19 ESI+: 688 822 P9  ESI+: 681 1 4 823 1 FAB+: 666 44 824 1 ESI+: 655 825 4 ESI+: 641 826 1 ESI+: 513 827 36 ESI+: 599 828 1 ESI+: 792 829 1 ESI+: 715 58 58 ESI+: 672 830 1 ESI+: 526 831 1 ESI+: 526 832 19 ESI+: 702 833 19 ESI+: 702 834 1 ESI+: 556 835 P33 ESI−: 601 1 836 1 ESI+: 644 837 1 ESI+: 567 838 58 ESI+: 595 839 11 ESI+: 580 840 35 ESI+: 596 841 1 ESI−: 680 842 1 FAB+: 605 843 1 ESI+: 721

TABLE 299 844 1 ESI+: 643 845 19 ESI+: 664 846 19 ESI+: 587 847 P33 FAB+: 541 1 848 1 FAB+: 587 849 1 FAB+: 587 850 1 FAB+: 587 851 1 FAB+: 587 852 1 ESI+: 701 853 58 ESI+: 581 854 1 FAB+: 591 855 1 FAB+: 591 856 4 ESI+: 674 NMR1: 1.00-2.30 (8H, m), 2.94 (3H, s), 3.58 (3H, s), 4.07 (1H, brs), 4.74 (1H, d, J = 11.0 Hz), 4.77 (1H, d, J = 11.0 Hz), 5.18 (1H, s), 6.36 (1H, d, J = 6.9 Hz), 6.88 (1H, d, J = 8.4 Hz), 7.08-7.11 (1H, m), 7.16 (1H, d, J = 2.0 Hz), 7.18 (1H, d, J = 2.0 Hz), 7.26 (2H, d, J = 8.0 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.43- 7.48 (2H, m), 7.64 (1H, d, J = 2.0 Hz) 7.93-7.96 (1H, m), 11.42 (1H, s), 12.34 (1H, brs) 857 1 FAB+: 616 858 1 ESI+: 627 859 19 ESI+: 571 860 1 ESI+: 540 861 1 ESI+: 513 862 1 ESI+: 545 863 1 ESI+: 564 864 1 ESI+: 589 865 1 ESI+: 537 866 1 ESI+: 532 867 1 ESI+: 505 868 1 ESI+: 616 869 1 ESI+: 548 870 1 ESI+: 574 871 1 FAB+: 564 872 1 FAB+: 532 873 1 ESI+: 542 874 1 ESI+: 573 875 1 ESI+: 608 876 21 ESI+: 598 877 1 FAB+: 728

TABLE 300 878 1 FAB+: 651 879 1 FAB+: 603 880 1 FAB+: 764 881 1 FAB+: 687 882 1 FAB+: 764 883 1 FAB+: 689 884 1 ESI+: 766 885 1 ESI+: 689 886 1 ESI+: 764 887 1 ESI+: 687 888 1 ESI−: 665 889 1 FAB+: 601 890 1 ESI+: 691 891 1 ESI+: 691 892 P9  ESI+: 678 1 893 1 ESI+: 714 894 1 FAB+: 637 895 1 FAB+: 758 896 1 ESI+: 758 897 1 FAB+: 636 898 P33 ESI+: 622 1 899 P33 APCI+: 435 1

TABLE 301 No Structure 1

2

3

4

TABLE 302 5

INDUSTRIAL APPLICABILITY

The compound (I) of the present invention as described above is useful as a therapeutic agent for the diseases in which BB2 receptors are related, in particular, for IBS since it has an excellent BB2 receptor antagonistic activity, and further, it exhibits excellent efficacy regarding bowel movement disorders. 

1. A tetrahydroisoquinolin-1-one derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof:

R¹: lower alkylene-OH, lower)alkylene-N(R⁰(R⁶), lower alkylene-CO₂R⁰, cycloalkyl, cycloalkenyl, aryl, heterocyclic group, -(lower alkylene substituted with —OR⁰)-aryl or lower alkylene-heterocyclic group, wherein the lower alkylene, cycloalkyl, cycloalkenyl, aryl and heterocyclic group in R¹ may each be substituted, R⁰: the same as or different from each other, each representing —H or lower alkyl, R⁶: R⁰, —C(O)—R⁰, —CO₂-lower alkyl or —S(O)₂-lower alkyl, R²: lower alkyl, lower alkylene-OR^(o), lower alkylene-aryl, lower alkylene-heterocyclic group, lower)alkylene-N(R⁰)CO-aryl, lower alkylene-O-lower alkylene-aryl, —CO₂R^(o), —C(O)N(R⁰)₂, —C(O)N(R⁰)-aryl,) —C(O)N(R⁰)-lower alkylene-aryl, aryl or heterocyclic group, wherein the aryl and heterocyclic group in R² may each be substituted, R³: —H or lower alkyl, or R² and R³ may be combined to form C₂₋₆ alkylene, R⁴: —N(R⁷)(R⁸), —N(R⁰)—OH, —N(R¹⁰)—OR⁷, —N(R⁰)—N(R⁰)(R⁷), —N(R⁰)—S(O)₂-aryl, or —N(R⁰)—S(O)₂—R⁷, wherein the aryl in R⁴ may be substituted, R⁷: lower alkyl, halogeno-lower alkyl, lower alkylene-CN, lower alkylene-OR⁰, lower alkylene-CO₂R⁰, lower)alkylene-C(O)N(R⁰)₂, lower alkylene-C(O)N(R⁰)N(R⁰)₂, lower alkylene-C(═NH)NH₂, lower alkylene-C(═NOH)NH₂, heteroaryl, lower alkylene-X-aryl, or lower alkylene-X-heterocyclic group, wherein the lower alkylene, aryl, heteroaryl, and heterocyclic group in R⁷ may each be substituted, X: single bond, —O—, —C(O)—, —N(R⁰), —S(O)_(p)—, or *-C(O)N(R⁰)—, wherein * in X represents a bond to lower alkylene, m: an integer of 0 to 3, p: an integer of 0 to 2, R⁸: —H or lower alkyl, or R⁷ and R⁸ may be combined to form lower alkylene-N(R⁹)-lower alkylene, lower alkylene-CH(R⁹)-lower alkylene, lower alkylene-arylene-lower alkylene, or lower alkylene-arylene-C(O)—, R⁹: aryl and heteroaryl which may each be substituted, R¹⁰: —H, lower alkyl, or —C(O)R⁰, R⁵: lower alkyl, halogeno-lower alkyl, halogen, nitro, —OR⁰, —O-halogeno-lower alkyl, —N(R⁰)₂, —O-lower alkylene-CO₂R⁰, or —O-lower alkylene-aryl, wherein the aryl in R⁵ may be substituted, provided that, when R⁴ is —N(R⁷)(R⁸), (1) a compound wherein R¹ is unsubstituted cyclopentyl and R² is unsubstituted 2-thienyl; (2) a compound wherein R¹ is unsubstituted cyclohexyl and R² is 4-methoxyphenyl; (3) a compound wherein R¹ is 4-methoxyphenyl and R² is 4-methoxyphenyl; and (4) a compound wherein R¹ is (morpholin-4-yl)ethyl and R² is 4-ethoxyphenyl are excluded, provided that, 2,3-bis(4-chlorophenyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, 3-(4-chlorobenzyl)-2-(4-chlorophenyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, 3-[3,5-bis(trifluoromethyl)phenyl]-2-cyclopropyl-N-(2-furylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, 3-[3,5-bis(trifluoromethyl)phenyl]-2-cyclopropyl-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, ethyl 3-{3-[3,5-bis(trifluoromethyl)phenyl]-4-{[2- (4-methoxyphenyl)ethyl]carbamoyl}-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl}propanoate, N-benzyl-3-[3,5-bis(trifluoromethyl)phenyl]-1-oxo-2-(tetrahydrofuran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, 3-[3,5-bis(trifluoromethyl)phenyl]-N-(2-methoxyethyl)-2-(2-morpholin-4-ylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, 3-[3,5-bis(trifluoromethyl)phenyl]-2-(2-furylmethyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, 3-[3,5-bis(trifluoromethyl)phenyl]-N-(2-furylmethyl)-2-(2-morpholin-4-ylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and (4-chlorophenyl)[3-(4-chlorophenyl)-4-[(2-methoxyethyl)carbamoyl]-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl]acetic acid are excluded].
 2. The compound as described in claim 1 or a pharmaceutically acceptable salt thereof, wherein R³ is —H.
 3. The compound as described in claim 2 or a pharmaceutically acceptable salt thereof, wherein R² is phenyl which may be substituted with halogen, lower alkyl, or —OR⁰.
 4. The compound as described in claim 3 or a pharmaceutically acceptable salt thereof, wherein R⁴ is —N(R⁰)-lower alkylene-(aryl or heteroaryl, which may each be substituted), or —N(R⁰)—O-lower alkylene-(aryl or heteroaryl, which may each be substituted).
 5. The compound as described in claim 4 or a pharmaceutically acceptable salt thereof, wherein R¹ is cycloalkyl substituted with a group selected from the group consisting of (lower alkylene which may be substituted with a group selected from the group consisting of phenyl which may be substituted with halogen, lower alkyl, or —OR⁰, and —OH)—OH; or —OR⁰, —N(R⁰)₂, —N(R⁰)C(O)R⁰, —N(R⁰)-lower alkylene-OR⁰, —N(R⁰)S(O)₂-lower alkyl, and heterocyclic group.
 6. The compound as described in claim 1, which is selected from the group consisting of: (3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S ,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S ,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-N-[(1- oxidopyridin-2-yl)methoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, 3-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S ,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}benzoic acid, (4-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S ,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenyl)acetic acid, (3-{[({[(3R,4R)-3-(2,4-dichlorophenyl-2-{(1S ,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetic acid, {3-[2-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S ,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]phenyl}(difluoro)acetic acid, (3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S ,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-N-(2-{3-[(methylsulfonyl)carbamoyl]phenyl}ethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, {4-[2-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S ,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]phenyl}acetic acid, and 4-(3-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S ,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)butanoic acid; or a pharmaceutically acceptable salt thereof.
 7. A pharmaceutical composition comprising the compound as described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 8. A method of antagonizing BB2 receptor, comprising administering the pharmaceutical composition as described in claim 7, to a patient in need thereof.
 9. A method of treating irritable bowel syndrome, comprising administering pharmaceutical composition as described in claim 7, to a patient in need thereof.
 10. A method for treating cancer, comprising administering the pharmaceutical composition as described in claim 7, to a patient in need thereof. 11-12. (canceled) 